The DOI matches its Crossref record; 47 of the 47 references it cites were found in a registry or an index; 4 of the 6 sources its claims cite were checked for support.
Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer
Open accessAbstract
Despite its success in achieving the long-term survival of 10-30% of treated individuals, immune therapy is still ineffective for most patients with cancer 1,2. Many efforts are therefore underway to identify new approaches that enhance such immune 'checkpoint' therapy 3-5 (so called because its aim is to block proteins that inhibit checkpoint signalling pathways in T cells, thereby freeing those immune cells to target cancer cells). Here we show that inhibiting PCSK9-a key protein in the regulation of cholesterol metabolism 6-8-can boost the response of tumours to immune checkpoint therapy, through a mechanism that is independent of PCSK9's cholesterol-regulating functions. Deleting the PCSK9 gene in mouse cancer cells substantially attenuates or prevents their growth in mice in a manner that depends on cytotoxic T cells. It also enhances the efficacy of immune therapy that is targeted at the checkpoint protein PD1. Furthermore, clinically approved PCSK9-neutralizing antibodies synergize with anti-PD1 therapy in suppressing tumour growth in mouse models of cancer. Inhibiting PCSK9-either through genetic deletion or using PCSK9 antibodies-increases the expression of major histocompatibility protein class I (MHC I) proteins on the tumour cell surface, promoting robust intratumoral infiltration of cytotoxic T cells. Mechanistically, we find that PCSK9 can disrupt the recycling of MHC I to the cell surface by associating with it physically and promoting its relocation and degradation in the lysosome. Together, these results suggest that inhibiting PCSK9 is a promising way to enhance immune checkpoint therapy for cancer.
Overview
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TL;DR
PCSK9 inhibition, via genetic deletion or clinically approved antibodies, potentiates anti-PD1 immune checkpoint therapy in murine tumors by increasing tumor-cell surface MHC I and cytotoxic T-cell infiltration, independent of cholesterol/LDLR regulation. PCSK9 physically promotes MHC I lysosomal degradation, and high tumor PCSK9 mRNA correlates with worse overall survival in TCGA cohorts.
Key findings
- PCSK9 knockout in B16F10, 4T1, MC38, and CT26 murine cancer cells attenuated tumor growth in syngeneic mice; this effect was absent in T/B/NK-deficient NCG mice and Rag1-deficient mice, and CD8+ T-cell depletion completely abolished the tumor growth delay.
- PCSK9 deficiency synergized with anti-PD1 therapy in all four tumor models; evolocumab or alirocumab plus anti-PD1 suppressed MC38 tumor growth and produced long-term survival in some mice, and evolocumab was effective in anti-PD1-resistant MC38R tumors but had no effect on PCSK9-deficient MC38 tumors.
- PCSK9 inhibition increased tumor cell surface MHC I (H2-Kb/SIINFEKL, H2b, H2d, HLA-A2), intratumoral CD8+ CTLs, CD4+ Th cells, γδT cells, NK cells, CTL/Treg ratios, IFNγ+ and GZMB+ CTLs, and TCR counts/diversity, without significant increases in Tregs or exhaustion markers.
- Mechanistically, PCSK9 bound H2-K1 via its M2 domain and H2-K1 aa68–70, promoting MHC I relocation to the lysosome and degradation; LDLR knockdown did not affect MHC I surface levels or the growth suppression caused by PCSK9 deficiency, and high PCSK9 mRNA was associated with worse overall survival in 9 TCGA cancer cohorts.
Methods
- Murine cancer cell lines (B16F10, 4T1, MC38, CT26) and human MDA-MB-231 cells were modified with CRISPR/Cas9 PCSK9 knockout, LDLR knockdown/knockout, or H2-K1 knockout/overexpression; in vitro growth and soft agar assays were used, and in vivo experiments used syngeneic C57BL/6J or Balb/c mice, NCG mice, Rag1−/− mice, LDLR−/− mice on high-fat diet, and OT-1 transgenic mice.
- Tumor growth delay, survival, in vivo competition, and re-challenge experiments were performed; treatments included anti-PD1 (clone RMP1–14), evolocumab, alirocumab, isotype controls, and antibody-mediated depletion of CD4+, CD8+, or NK cells.
- Analyses included flow cytometry, immunofluorescence, qRT-PCR, TCR sequencing, co-immunoprecipitation, cell fractionation, cycloheximide chase, and bafilomycin treatment; human correlations used GENT for PCSK9/CD8A and TCGA/cBioPortal for PCSK9 mRNA and overall survival, with two-way ANOVA, log-rank tests, and unpaired two-sided t tests.
Limitations
- The paper states that no randomization or blinding was used in the tumor growth delay experiments.
- The paper has no explicit limitations section; evident from the text, the efficacy and mechanistic findings are primarily preclinical in murine tumor models and cell lines, and the human evidence is correlative (GENT/TCGA), not from a clinical trial of PCSK9 inhibition plus checkpoint blockade.
- Also evident, several mechanistic domain-mapping experiments rely on overexpression or deletion mutants in 293T/B16F10 cells, which may not fully reflect endogenous PCSK9–MHC I interactions.
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Claims the paper makes
78 Own result · 19 Own method · 19 Own interpretation · 2 Partly supported · 2 No full text of the sources · 1 Supported · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
In the paper
“deletions of the other two domains (M1 & M3) and the aa367–386 domain, which was involved in LDLR binding34, in the catalytic region, also showed reduced H2-K1 binding”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
What the sources say
- Supportedcites [34] Duff, C. J. et al. Antibody-mediated disruption of the interaction between PCSK9 and the low-density lipoprotein receptor. Biochem. J. 419, 577–584 (2009). source
The citation is attached to the LDLR-binding description, not the claim about reduced H2-K1 binding. In Results (page unavailable), the paper places an overlapping PCSK9 region, aa 365–384, in the catalytic domain near Asp374 and describes it as critical to interaction with LDLR; antibodies against that region reduced PCSK9–LDLR binding. The paper gives slightly different residue boundaries from aa 367–386. (LLM, conf=0.86)
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In the paper
“Previous studies have demonstrated that the amount of active T-cells is positively correlated with the success of immune checkpoint blockade therapy36,37”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Discussion
What the sources say
- Partly supportedcites [36] Zhang, L. et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 348, 203–213 (2003). sourceExperimental — accuracy not yet measured
The ‘Intratumoral T Cells and Clinical Outcome’ section reports that patients with intratumoral T cells had longer progression-free and overall survival, and the discussion describes evidence that those T cells were activated. The paper does not examine immune checkpoint blockade or show that the amount of active T cells predicts its success; its finding concerns T-cell presence and outcomes in ovarian cancer. (LLM, conf=0.86)
- Partly supportedcites [37] Carstens, J. L. et al. Spatial computation of intratumoral T cells correlates with survival of patients with pancreatic cancer. Nat. Commun. 8, 15095 (2017). sourceExperimental — accuracy not yet measured
The Abstract links endogenous antitumour T cells to the efficacy of therapies combined with checkpoint blockade. But it does not report a positive correlation between the amount of active T cells and checkpoint-blockade success. The Discussion states that T-cell functional status was not measured; page numbers are unavailable in our copy. (LLM, conf=0.86)
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In the paper
“anti-PD1 therapy was ineffective, as reported before29”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
What the sources say
- Partly supportedcites [29] Kim, K. et al. Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc. Natl Acad. Sci. USA 111, 11774–11779 (2014). sourceExperimental — accuracy not yet measured
The Effects of Immune Checkpoint Blockade section describes 4T1 tumors as resistant to immunotherapy, and the Discussion says combined anti-PD-1/anti-CTLA-4 treatment generally could not cure them. The copy does not explicitly report the outcome of anti-PD-1 alone in 4T1 mice; moreover, 3 of 10 mice had complete primary-tumor regression with the combination, so “ineffective” needs qualification. (LLM, conf=0.79)
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“It also enhanced the efficacy of anti-PD1 immune checkpoint therapy significantly.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Abstract
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“clinically approved PCSK9-neutralizing antibodies could synergize with anti-PD1 therapy in suppressing tumor growth in murine tumor models”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Abstract
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“PCSK9 inhibition, either through genetic deletion or PCSK9 antibodies, caused a significant increase in tumor cell surface major histocompatibility protein class I (MHC I) expression”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Abstract
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“Deletion of the PCSK9 gene in murine cancer cells significantly attenuated or prevented their growth in mice”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Abstract
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“in a cytotoxic T-cell-dependent manner”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Abstract
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“depletion of CD4+ T cells or NK cells only had marginal effects”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
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“patients with high tumor PCSK9 mRNA expression had worse overall survival than those with low expression in 9 different TCGA (The Cancer Genome Atlas) patient cohorts”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
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“the dominant clones in PCSK9-deficient tumors were different from those in control tumors”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
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“their abilities to form tumors were significantly attenuated in comparison to vector controls”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 deficiency and tumor growth rate
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“evolocumab treatment of murine 4T1 tumors also boosted MHC-I levels on the surface of 4T1 cells”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
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“PCSK9 mRNA expression was negatively correlated with expression of CTL marker CD8A in several human malignancies”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
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“NK cells (Fig. 3d)”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
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“LDLR knockdown did not diminish the growth suppression caused by PCSK9 deficiency in B16F10 tumors”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
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“measurement of T cell exhaustion markers showed no significant changes”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
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“reintroduction of PCSK9 into the PCSK9KO B16F10 cells rescued tumorigenic abilities of the PCSK9KO B16F10 cells”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 deficiency and tumor growth rate
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“a significant fraction of long-term survivors of 4T1-PCSK9KO tumors (Extended Data Fig. 5a–c), B16F10-PCSK9KO tumors (Extended Data Fig. 5d–f), and MC38-PCSK9KO tumors (Extended Data Fig. 5g–i), rejected the WT tumor cell re-challenge”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 inhibition and immunotherapy
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“both the numbers and percentages of IFNγ+, or Granzyme B+ (GZMB+) CTLs also increased significantly in PCSK9-deficient tumors”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
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“Neither did it have any influence on MHC I expression on the surface of B16F10 cells”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
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“re-introduction of the H2-K1Δ68–70 did not slow down tumor growth”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
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“LDLR deficiency in the tumor cells did not have any significant effect on tumor growth”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 inhibition and immunotherapy
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“absence of the α1 region (aa66–100) and in particular, of amino acids aa68–70, which sits in the loop right before the helix structure of the α1 domain35, completely abolished binding to PCSK9”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
What the sources say
- Not checked — no full text of the sourcecites [35] Yu, Y. Y. et al. Definition and transfer of a serological epitope specific for peptide-empty forms of MHC class I. Int. Immunol. 11, 1897–1906 (1999). source
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“or incubated with anti-PCSK9 antibodies”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
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“no increases in CD4+ or CD8+ T-cells were observed in the spleen of host mice”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
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“total TCR counts (Fig. 3k) and the number of unique TCRs (Fig. 3l) were significantly increased in PCSK9-deficient tumors”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
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“incubation of exogenous PCSK9 protein with PCSK9-deficient MDA-MB-231 cells caused a decrease in surface HLA-A2 levels”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
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“anti-PD1 antibody synergized with PCSK9 deficiency in all four models”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 inhibition and immunotherapy
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“total TCR counts (Fig. 3k) and the number of unique TCRs (Fig. 3l) were significantly increased in PCSK9-deficient tumors”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
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“and CD8+ cells (Extended Data Fig. 6b)”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
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“Flow cytometry analyses confirmed significant increases in intratumoral CD8+ cytotoxic T cells (CTLs) (Fig. 3a)”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
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“CD4+ T helper (Th) cells (Fig. 3b)”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
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“depletion of CD8+ T cells completely abolished the tumor growth delay of PCSK9-deficient tumors”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
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“The ratios of CTLs vs Tregs in the PCSK9-deficient tumors were significantly increased”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
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“genetic depletion of H2-K1 abrogated tumor growth delay induced by PCSK9 inhibition”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
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“PCSK9 deficiency had no effect on tumor growth in NCG mice”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 deficiency and tumor growth rate
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“administration of the anti-PCSK9 antibodies alone delayed tumor growth of MC38 tumors”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 inhibition and immunotherapy
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“evolocumab had no effect on tumor growth in PCSK9-deficient MC38 tumors”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 inhibition and immunotherapy
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“no significant increases in CD4+Foxp3+ regulatory T (Treg) cells were observed”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
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In the paper
“tumor cell surface MHC I expression was significantly increased in PCSK9-deficient tumors when compared with control”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
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In the paper
“In PCSK9OE cells, more H2-K1 was localized in the lysosome and not in the plasma membrane”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
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In the paper
“In the absence of de novo protein synthesis (cycloheximide), HLA-ABC levels in PCSK9KO MDA-MB-231 cells declined significantly slower compared to control cells”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
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In the paper
“as well as intratumoral expression of IFNG and GZMB (qRT-PCR, Extended Data Fig. 6e, f)”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
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In the paper
“PCSK9 depletion caused an overall increase in intratumoral infiltration of CD45+ leukocytes”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
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In the paper
“in PCSK9KO cells, H2-K1 staining indicated a more plasma membrane localization”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
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In the paper
“productive clonality, a measurement of the dominance of individual T-cell clones, was elevated in PCSK9-deficient tumors”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
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In the paper
“only had a marginal effect on PD-L1 expression in B16F10 cells”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
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In the paper
“absence of the α1 region (aa66–100) and in particular, of amino acids aa68–70, which sits in the loop right before the helix structure of the α1 domain35, completely abolished binding to PCSK9”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
What the sources say
- Not checked — no full text of the sourcecites [35] Yu, Y. Y. et al. Definition and transfer of a serological epitope specific for peptide-empty forms of MHC class I. Int. Immunol. 11, 1897–1906 (1999). source
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In the paper
“H2-Kb/SIINFEKL staining was significantly enhanced on the surface of IFNγ-stimulated PCSK9-deficient B16F10-OVA cells when compared with control B16F10-OVA cells”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
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In the paper
“deletion of M2 domain within the C-terminal region PCSK9 showed almost complete loss of binding to H2-K1”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
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In the paper
“the maximum dominance of individual T-cell clones in both control and PCSK9-deficient tumors was close to 20–30%”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
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In the paper
“only the presence of evolocumab could boost the number of active IFNγ+ CTLs”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
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In the paper
“PCSK9 deficiency did not influence B16F10 tumor formation in Rag1-deficient mice”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 deficiency and tumor growth rate
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In the paper
“γδT cells (Fig. 3c)”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
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In the paper
“the attenuation in tumor growth from PCSK9 deficiency was not affected by host LDLR status or cholesterol levels”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 inhibition and immunotherapy
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In the paper
“PCSK9 deficiency also caused a significant increase in H2d MHC I alloantigens in IFNγ-treated 4T1 cells in vitro”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
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In the paper
“increased human leukocyte antigen (HLA)-A2 levels in human breast cancer line MDA-MB-231 with PCSK9KO”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“PCSK9 deficiency failed to show any effect on MHC II expression”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
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In the paper
“re-introduction of WT H2-K1 gene attenuated the tumor-forming abilities of both H2-K1 deficient and PCSK9/H2-K1DKO cells”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
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In the paper
“LDLR knockout did not affect the up-regulation of surface MHC I expression induced by PCSK9 deficiency”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
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In the paper
“both the numbers and percentages of IFNγ+, or Granzyme B+ (GZMB+) CTLs also increased significantly in PCSK9-deficient tumors”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
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In the paper
“it also had clear anti-tumor efficacy in this model”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
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In the paper
“in C57BL/6 mice that remained tumor-free 34 days after initial challenge with PCSK9-deficient MC38 cells and the treatment with anti-PD1 antibody.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
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In the paper
“in C57BL/6 mice that remained tumor-free 26 days after initial challenge with PCSK9 deficient B16F10 cells and the treatment with anti-PD1 antibody.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
plainn = 13- Asserted: passes — The authors put it forward as true.
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In the paper
“ns: not significant. n=5 tumors per group.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
plainn = 5- Asserted: passes — The authors put it forward as true.
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In the paper
“ns: not significant, as determined by two-way ANOVA (d,g), log-rank test (e,h), or unpaired two- sided t test (f, i).”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
plainn = 5- Asserted: passes — The authors put it forward as true.
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In the paper
“Enhanced presentation of OVA antigen (SIINFEKL) by MHC-I in cultured B16F10 cells with PCSK9 deficiency.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
plaindirectn = 4- Asserted: passes — The authors put it forward as true.
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In the paper
“in Balb/c mice that remained tumor-free 43 days after initial challenge with PCSK9 deficient 4T1 cells.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
plainn = 12- Asserted: passes — The authors put it forward as true.
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In the paper
“ns: not significant, as determined by two-way ANOVA (d,g), log-rank test (e,h), or unpaired two- sided t test (f, i).”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
plainn = 6- Asserted: passes — The authors put it forward as true.
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In the paper
“ns: not significant, as determined by two-way ANOVA (d,g), log-rank test (e,h), or unpaired two- sided t test (f, i).”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
plainn = 6- Asserted: passes — The authors put it forward as true.
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In the paper
“ns: not significant. n=5 tumors per group.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
plainn = 5- Asserted: passes — The authors put it forward as true.
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In the paper
“which promoted robust intratumoral infiltration of cytotoxic T-cells”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Abstract
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In the paper
“PCSK9 could disrupt the recycling of MHC I to the cell surface by promoting its relocation and degradation in the lysosome through physical association”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Abstract
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In the paper
“albeit through a mechanism independent of its cholesterol regulating functions”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Here we show that inhibition of PCSK9, a key protein in regulating cholesterol metabolism6–8, can boost tumor response to immune checkpoint therapy”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“These results demonstrated that PCSK9 had a strong influence on MHC I presentation of peptide antigens”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
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In the paper
“indicating an anti-tumor immune memory”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 inhibition and immunotherapy
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“antibody-mediated PCSK9 neutralization could enhance anti-PD1 therapy in murine tumor models”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 inhibition and immunotherapy
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“which suggests that a few T-cell clones accounted for 30% of all intratumoral T-cell population”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“Our results thus suggest that PCSK9 down-regulates MHC I surface levels in a manner similar to its negative regulation of LDLR by lysosome-mediated degradation”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“indicating significant expansion and dominance of a subset of T-cell clones”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“indicating tumor cell intrinsic rather than host PCSK9 was important for antitumor efficacy of evolocumab”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 inhibition and immunotherapy
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“thereby suggesting a key role for PCSK9 in regulating HLA-ABC levels through lysosome-mediated degradation”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Our results therefore established H2-K1 as an essential downstream factor of PCSK9 in regulating tumor growth”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
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In the paper
“In the presence of PCSK9, MHC I is transported into the lysosome and degraded (left panel).”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“PCSK9 inhibitors may enhance immune checkpoint blockade therapy without additional side effects”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: Combining PCSK9 inhibitors with immune checkpoint blockade will not add side effects.
- It may state two separate claims as one. 14
- The quote only partly states this claim. 12
- Probably not a substantial claim. 19
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In the paper
“PCSK9 knockout (PCSK9KO) did not alter the morphology or the in vitro growth rates of tumor cells”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 deficiency and tumor growth rate
plainn = 4- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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In the paper
“both anti-PD1 and anti-PCSK9 antibodies could boost the numbers of CTLs inside the tumor”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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In the paper
“Our results indicated that PCSK9 more susceptible to killing by CTLs”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
hedgeddirect- Asserted: passes — The authors put it forward as true.
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The quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“re-introduction of the wild type PCSK9 abolished the tumor growth delay while that of PCSK9ΔM2 had no effect”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“H2-K1 expression could significantly attenuate tumor growth alone or in combination with anti-PD1”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“when the cells were exposed to bafilomycin to inhibit lysosome function, the levels of HLA-ABC increased significantly in control cells but did not change much in PCSK9KO cells”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Evolocumab treatment was effective either alone or in combination with anti-PD1 treatment for MC38R tumors”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 inhibition and immunotherapy
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, in the membrane fraction, PCSK9OE reduced the relative abundance of the H2-K1 protein while PCSK9 knockout increased it”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“CD8+ cells staying mostly in the periphery in control tumors (Extended Data Fig. 6b, top panels) but moving into tumor cell-rich areas in the PCSK9-deficient B16F10 tumors”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the lysosome fraction, PCSK9 OE caused an increase in H2-K1 protein while PCSK9KO induced a decrease”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“their efficacies were enhanced significantly when combined with an anti-PD1 antibody, with long-term survival of some host mice”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 inhibition and immunotherapy
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It suggests that PCSK9 neutralization may promote intratumoral T cell infiltration and thus render tumors more responsive to immune checkpoint therapy”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results suggest that both the number and diversity of mature T-cells were significantly elevated in PCSK9-deficient tumors”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The finding that PCSK9 plays important roles in regulating cell surface MHC I levels (see Extended Data Fig. 10 for a summary schema) and thus influences intratumoral immune infiltration is novel mechanistically”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The analyses were repeated twice with biologically independent samples with similar results.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All animal experiments conducted in this study were approved by Duke University Institutional Animal Use and Care Committee (IACUC)”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Methods > Tumor growth in mice.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The analysis was done once.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
plain- Asserted: fails — The authors may not put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. The quote only partly states this claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Their identities were verified by the STR method”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Methods > Cell lines.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All cell lines were subjected to mycoplasma test periodically”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Methods > Cell lines.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“expression of target protein (PCSK9) in infected cells were detected by western blot to verify the knockdown”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Methods > CRISPR/Cas9-mediated gene knockout.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“At least 5 mice per treatment group were included”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Methods > Tumor growth in mice.
plainn = 5- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Original uncropped images highlighting the cropped areas were shown in Supplementary Data Fig. 1”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Methods > Western blot analysis.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The analysis was done once.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
plain- Asserted: fails — The authors may not put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. The quote only partly states this claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The experiments were completed twice with similar results.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Shown were representative results from analyses of 4 sets of biologically independent samples.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
plainn = 4- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The analyses were done twice.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The analyses were repeated twice with biologically independent samples with similar results.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Two independent experiments were carried out”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Methods > Soft agar colony formation assay.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The analyses were repeated twice with biologically independent samples with similar results.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The analysis was done once.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the absence of PCSK9, either because of genetic deletion or antibody neutralization, MHC I levels on the surface remains high and is thus able to present tumor-specific peptic antigens more efficiently to T cells (right panel).”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The analysis was done once.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Analysis was done twice with biologically independent samples.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
plainn = 2- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“No randomization or blinding was used in our tumor growth delay experiments”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Methods > Tumor growth in mice.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
Findings from murine tumor models and cell lines will translate to human cancer patients.
“provide compelling rationales for conducting future clinical trials in human cancer patients”
The paper relies on this without support.
Combining PCSK9 inhibitors with immune checkpoint blockade will not add side effects.
“Given the well-known safety profiles of the anti-PCSK9 antibodies, PCSK9 inhibitors may enhance immune checkpoint blockade therapy without additional side effects.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
“Furthermore, LDLR knockout did not affect the up-regulation of surface MHC I expression induced by PCSK9 deficiency (Extended Data Fig. 8j).”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
“j. Flow cytometry analysis of MHC I expression in tumors formed from tdTomato-labeled LDLRKD (n=6) and LDLRKD/PCSK9KO cells (n=4).”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
“b-c. Tumor growth delay (b) and Kaplan-Meier survival curve (c) of tumor-bearing C57BL/6 mice implanted with vector control or H2-K1 over-expression B16F10 cells.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
“d-e. Tumor growth delay (d) and Kaplan-Meier survival curves (c) in mice injected with vector control, H2-K1 KD, PCSK9 KO, or H2-K1KD/PCSK9KO B16F10 cells.”
Citations
Cites
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Multiplex Genome Engineering Using CRISPR/Cas Systems
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Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal
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Safety, activity, and immune correlates of anti–PD-1 antibody in cancer
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Genome engineering using the CRISPR-Cas9 system
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Genome-scale CRISPR-Cas9 knockout screening in human cells
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Nivolumab plus Ipilimumab in Advanced Melanoma
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Intratumoral T Cells, Recurrence, and Survival in Epithelial Ovarian Cancer
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T cell receptor antagonist peptides induce positive selection.
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Cited by
Sorted by citations
Turning cold tumors into hot tumors by improving T-cell infiltration
Liu, Y., & Sun, Z. (2021) · Theranostics · doi:10.7150/thno.58390 · Cited by 867
The hallmarks of cancer immune evasion
Galassi, C., Chan, T. A.-T., Vitale, I., & Galluzzi, L. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.09.010 · Cited by 630
Current advance of nanotechnology in diagnosis and treatment for malignant tumors
Wang, B., Hu, S., Teng, Y., Chen, J., Wang, H., Xu, Y., Wang, K., Xu, J., Cheng, Y., & Gao, X. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01889-y · Cited by 641
Lipid metabolic reprogramming in tumor microenvironment: from mechanisms to therapeutics
Jin, H.-R., Wang, J., Wang, Z., Xi, M., Xia, B., Deng, K., & Yang, J. (2023) · Journal of Hematology & Oncology · doi:10.1186/s13045-023-01498-2 · Cited by 537
“Moreover, inhibiting PCSK9, a key protein in the regulation of cholesterol metabolism, can boost the response of tumors to immune checkpoint therapy [317].”
BackgroundFu, T., Dai, L.-J., Wu, S.-Y., Xiao, Y., Ma, D., Jiang, Y.-Z., & Shao, Z.-M. (2021) · Journal of Hematology & Oncology · doi:10.1186/s13045-021-01103-4 · Cited by 480
“Spatial architecture of the TIME in clinical treatment To remodeling the spatial architecture of the TIME, diverse therapeutic strategies have also been proposed, including those that promote (116, 198) or prevent (199) immune cells from infiltrating into designated areas of the TIME, modify angiogenesis or oxygenatio…”
Method
Metadata
- Authors
- Liu, X., Bao, X., Hu, M., Chang, H., Jiao, M., Cheng, J., Xie, L., Huang, Q., Li, F., & Li, C.-Y.
- Affiliations
- Sun Yat-sen University (CN)
- Duke Medical Center (US)
- Shanghai Jiao Tong University (CN)
- Fudan University (CN)
- Duke University (US)
- Corresponding author
- Li, Chuan-Yuan
- Venue
- Nature
- Published
- 2020-11-11
- Volume
- 588
- Issue
- 7839
- Pages
- 693-698
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7770056
- OpenAlex
- W3103804121
- Cited by
- 490
- References
- 47
- Citations by year
- 2026: 60 · 2025: 107 · 2024: 106 · 2023: 81 · 2022: 73 · 2021: 60 · 2020: 2
- FWCI
- 17.32
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (2p30ca014236-51)
- National Cancer Institute (P30‐CA014236, R01 CA208852, R01CA216876)
- National Institute of Environmental Health Sciences (R01ES024015)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- PCSK9 inhibition, immune checkpoint therapy, anti-PD-1 therapy, cancer immunotherapy, cytotoxic T lymphocytes, tumor surveillance, lysosomal degradation, antigen presentation, tumor growth inhibition
- MeSH terms
- Proprotein Convertase 9, Immune Checkpoint Inhibitors, PCSK9 Inhibitors, Animals, Disease Models, Animal, Female, Humans, Immunotherapy, Lysosomes, Neoplasms, T-Lymphocytes, Cytotoxic, Histocompatibility Antigens Class I, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Antibodies, Neutralizing, Programmed Cell Death 1 Receptor
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-19, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-19 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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