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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Written from the paper’s full text.
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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In the paper
“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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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
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“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
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“Our results indicated that PCSK9 more susceptible to killing by CTLs”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
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“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
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“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
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“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
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“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
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“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
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“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
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“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
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“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
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“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
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“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
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“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
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“The analyses were repeated twice with biologically independent samples with similar results.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
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“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.
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“The analysis was done once.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
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“Their identities were verified by the STR method”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Methods > Cell lines.
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“All cell lines were subjected to mycoplasma test periodically”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Methods > Cell lines.
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“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.
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“At least 5 mice per treatment group were included”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Methods > Tumor growth in mice.
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“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.
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“The analysis was done once.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
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“The experiments were completed twice with similar results.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
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“Shown were representative results from analyses of 4 sets of biologically independent samples.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
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“The analyses were done twice.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
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“The analyses were repeated twice with biologically independent samples with similar results.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
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“Two independent experiments were carried out”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Methods > Soft agar colony formation assay.
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- 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
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Cited by
Sorted by citations
Items 301–400 of 490
Ubiquitination in lipid metabolism reprogramming: implications for pediatric solid tumors
Zhang, W., Xu, Y., Fang, Y., Li, M., Li, D., Guo, H., Li, H., He, J., & Miao, L. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1554311 · Cited by 7
“Cholesterol metabolism plays a critical role in pediatric tumor progression by supporting rapid cell proliferation (83), immune evasion (84, 85), and therapy resistance (86).”
27-Hydroxycholesterol in cancer development and drug resistance
Hou, Y., Fu, Z., Wang, C., Kucharzewska, P., Guo, Y., & Zhang, S. (2025) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.1080/14756366.2025.2507670 · Cited by 5
“240,241 However, since these approaches also affect systemic cholesterol homeostasis, comprehensive preclinical studies are needed to assess their safety and therapeutic potential.”
Jia, W., Yang, W., Wu, Y., Ren, H., Jia, Y., Ye, W., Xie, Y., Chen, Y., & Yu, M. (2025) · Journal of the American Chemical Society · doi:10.1021/jacs.5c06120 · Cited by 7
Disruption of cell-intrinsic PCSK9 enhances the antitumor efficacy of CD8 + T cells
Liu, B., Cai, L., Yan, Y., Mao, C., Zhang, X., He, Y., Chen, S., Liu, L., Xu, Z., Xu, L., et al. (2025) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2025-011657 · Cited by 5
“12 18 Mechanistically, tumor cell-derived PCSK9 promotes tumor immune escape by reducing major histocompatibility complex class I (MHC I) on the tumor cell surface 19 and preventing LDLR-mediated T-cell receptor (TCR) recycling.”
Chen, L., Hu, M., Yan, H., Ding, X.-Q., Yang, Q.-X., Wang, L., & Pan, H. (2025) · Materials Today Bio · doi:10.1016/j.mtbio.2025.102329 · Cited by 5
“This process results in decreased MHC-I expression on the surface of tumor cells, thereby hindering T cell-mediated recognition and contributing to the immune evasion of cancer cells [11,12].”
Self-citationLipid metabolic reprogramming in colorectal cancer: Insights to mechanisms and therapeutics
Wang, C.-D., Zhang, B., & Song, J. (2025) · World Journal of Gastrointestinal Oncology · doi:10.4251/wjgo.v17.i10.109398 · Cited by 7
Huang, Z.-J., Xu, J., Wang, Y., Fu, Z., Zhang, Y., Zhao, Q., Zhang, R., Hu, X., Cheng, X., & Hu, C. (2025) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2025.105057 · Cited by 5
Hu, C., Qin, M., Lai, W., Zhou, H., Yuan, C., Liu, Y., Dai, Y., Yang, M., Hu, M., Wang, X., et al. (2025) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2025-012586 · Cited by 5
Self-citationXiang, J., Wang, T., Tian, S., Li, J., Luo, M., Wang, Y., Du, A., Chen, X., Tian, F., Wang, L., et al. (2026) · Nature Cell Biology · doi:10.1038/s41556-026-01926-8 · Cited by 5
Peptide-MHC I regulatory mechanisms and intervention strategies in anti-tumor T cell immunity
Zhang, Z., Shen, Y. J., Lin, Y.-S., Yang, B., Cao, J., Li, J., & Zhao, W. (2025) · Acta Pharmacologica Sinica · doi:10.1038/s41401-025-01574-y · Cited by 5
“For example, PCSK9 could disrupt the recycling of MHC-I to the cell surface by promoting its relocation and degradation in the lysosome through physical association [70].”
A novel tumor 4-driver gene signature for the prognosis of hepatocellular carcinoma
Guo, H., Lu, F., Lu, R., Huang, M., Li, X., Yuan, J., & Wang, F. (2023) · Heliyon · doi:10.1016/j.heliyon.2023.e17054 · Cited by 5
“A series of researches in some different cancers have revealed connectivity between the tumor immune infiltrating cell square measure and immune checkpoint therapy response [55,56].”
BackgroundMikaeeli, S., Ouadda, A. B. D., Evagelidis, A., Essalmani, R., Ramos, O. H. P., Fruchart‐Gaillard, C., & Seidah, N. G. (2024) · Cells · doi:10.3390/cells13100857 · Cited by 6
“In contrast to HFE and in agreement with a previous study [16], HLA-C degradation by PCSK9 does not require the LDLR (Figure 4F).”
BackgroundResultInfluentialGhalali, A., Alhamdan, F., Upadhyay, S., et al. (2024) · Communications Biology · doi:10.1038/s42003-024-06674-9 · Cited by 5
“PCSK9inducedproin fl ammatorycytokinesinmacrophages 8 and PCSK9inhibitionenhancedimmunecheckpointtherapyagainstcancer 9 .”
Mellor, R., Ardolino, L., Scheinberg, T., Fitzpatrick, M., Lin, H., Bonnitcha, P., Sullivan, D., Meikle, P. J., Stockler, M. R., Moujaber, T., et al. (2024) · Therapeutic Advances in Medical Oncology · doi:10.1177/17588359241307814 · Cited by 5
“18,19 We have developed a plasma lipid biomarker assay named PCPro, which incorporates prognostic sphingolipids and is able to prospectively identify men with who are more likely to be abiraterone or enzalutamide-resistant (median OS 31.5 months in men treated with an ARPI who were PCPro negative…”
InfluentialWood, C., Lyniv, L., Isaacs, J. M., Kaufman, J. M., Oduah, E., Clarke, J., Crawford, J., Stinchcombe, T. E., Tong, B. C., Wang, X., et al. (2025) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2024-010395 · Cited by 6
Ha, C. S. R., Müller‐Nurasyid, M., Petrera, A., Hauck, S. M., Marini, F., Bartsch, D. K., Slater, E. P., & Strauch, K. (2023) · PLoS ONE · doi:10.1371/journal.pone.0280399 · Cited by 5
“also proposed that immune checkpoint therapy for cancer may benefit from inhibition of PCSK9 [54,55].”
BackgroundInfluentialYang, L., Pan, M., Hu, H., Liu, F., Jiang, M., Ning, S., Chen, X., Zhang, Z., Yu, X., & Xu, L. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.08.12.607118 · Cited by 5
Kuang, J. C., Hao, L., Zhang, M., & Yang, Z. (2025) · MedComm · doi:10.1002/mco2.70451 · Cited by 7
Wang, W.-L., Yen, C., Yen, C.-S., Huang, Y.-H., Huang, H.-Y., Chen, J.-F., Liu, Y.-T., Wang, S.-T., Liu, Y., Hung, M., et al. (2026) · Cancer Letters · doi:10.1016/j.canlet.2026.218255 · Cited by 4
Cholesterol metabolism in immune cells: From mechanisms to therapeutic opportunities
Yin, M., Liang, T., Zhang, Y., Wang, G., Yang, W., & Xu, C. (2026) · Immunity · doi:10.1016/j.immuni.2026.05.007 · Cited by 5
Gao, X., Yi, L., Fu, S., Lu, Z., Wang, J., & Zhang, S. (2024) · Journal of Surgical Research · doi:10.1016/j.jss.2024.06.005 · Cited by 4
Serum PCSK9 is a novel serological biomarker for the diagnosis and prognosis of pancreatic cancer
Xu, Y. C., Xu, Y., Yang, Y., et al. (2024) · PeerJ · doi:10.7717/peerj.18018 · Cited by 4
“PCSK9 binds to the LDLR to regulate lipoprotein homeostasis and immune checkpoints in cancer ( Liu et al., 2020 ; Schulz, Schluter & Laufs, 2015 ; Yuan et al., 2021 ).”
BackgroundGathers, D., Oswalt, C. J., Alder, L., Chen, K. Y., Higgins, J. P., Clarke, J. M., & Oduah, E. (2025) · Cancers · doi:10.3390/cancers17132077 · Cited by 4
Singh, K., Foster, M. W., Violette, M. J., Corcoran, A. M., Hotchkiss, K. M., Railton, C. O., Blandford, E. E., Blethen, K. E., Thomas, E. L., McIntosh, W. C., et al. (2025) · Scientific Reports · doi:10.1038/s41598-025-21064-9 · Cited by 4
Self-citationLZTR1 regulates epithelial MHC-I expression via NF-κB1 to modulate CD8+ T cells activation
Jiang, R., Fang, Z., Wang, Y., Huang, B. S., Liu, J., Tsoi, L. C., Wasikowski, R., Zhang, Z., Kuang, Y., Li, X. Z., et al. (2025) · Cell Discovery · doi:10.1038/s41421-025-00837-6 · Cited by 4
“The roles of MHC-I, including HLA-A/B/C, are well-established in tumor biology 56 – 58 , where IFN γ , secreted by tumor-in fi ltrating T cells, can induce expression of MHC-I on tumor cells and boost CD8 + T cells cytotoxicity 59 .”
Optimization of Hypercholesterolemia Treatment after Heart Transplant: The Role of PCSK9 Inhibitors
Valero‐Masa, M. J., Ortiz‐Bautista, C., Castrodeza, J., & Martínez‐Sellés, M. (2024) · Current Pharmaceutical Design · doi:10.2174/0113816128315228240716183827 · Cited by 4
Xu, G., Chu, M., Shen, S., et al. (2024) · Archives of Dermatological Research · doi:10.1007/s00403-024-03635-4 · Cited by 4
“Neutralizing PCSK9 may enhance T-cell infiltration into tumors, increasing tumor sensitiv - ity to these therapies [ 34].”
Self-citationAntipenko, I. D., Olkhovik, D. M., Солопова, О. Н., et al. (2025) · Current Medicinal Chemistry · doi:10.2174/0109298673291217241219055416 · Cited by 4
Targeting PCSK9 beyond the liver: evidence from experimental and clinical studies
Dalt, L. D., Baragetti, A., & Norata, G. D. (2025) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2025.2482545 · Cited by 4
“…Lipoprotein Receptor (VLDLR) [2], Apolipoprotein E Receptor 2 (ApoER2), Low-Density Lipoprotein-Related Protein 1 (LRP-1) [3], the scavenger receptor, Cluster of Differentiation 36 (CD36) [4], the epithelial sodium channel (ENaC) [5], and the major histocompatibility type I receptor (MHC-I) [6].”
A Critical Review of Immunomodulation in the Management of Inoperable Stage III NSCLC
Burcher, K. M., Karukonda, P., Kelsey, C. R., Mullikin, T. C., Antonia, S. J., & Oduah, E. (2025) · Cancers · doi:10.3390/cancers17111829 · Cited by 4
Blocking PCSK9 enhances immune checkpoint therapy
Crunkhorn, S. (2020) · Nature Reviews Drug Discovery · doi:10.1038/d41573-020-00208-8 · Cited by 4
Zhang, P., Xu, Y., Zhang, L., et al. (2021) · Research Square · doi:10.21203/rs.3.rs-835938/v1 · Cited by 4
Wang, Z., Li, X., & Sun, X. (2025) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2025.189422 · Cited by 2
Wang, C., Xing, J., Zhao, H., Chen, X., Niu, Z., Ma, X., Gui, Y., Qi, X., Shi, Y., Cheng, X., et al. (2025) · Bioengineering & Translational Medicine · doi:10.1002/btm2.70076 · Cited by 5
Su, N. Y., Lian, W., Zhang, B., Tian, Y., Li, L., Chen, Y., Zhi, X., Zeng, T., Wu, Q., Chen, L., et al. (2025) · Cell Reports Medicine · doi:10.1016/j.xcrm.2025.102420 · Cited by 3
Mei, W., Ding, Y., Bian, C., Jia, Y., Qu, C. F., Fang, Z., Li, J., Liu, S., Sun, H., Xu, X., et al. (2025) · Journal of Advanced Research · doi:10.1016/j.jare.2025.10.079 · Cited by 3
“Emerging evidence indicates that proprotein convertase subtilisin/kexin type 9 (PCSK9) impairs MHC-I recycling in neoplastic cells through lysosomal degradation pathways [19], while autophagic machinery facilitates pancreatic cancer immune escape via proteolytic elimination of MHC-I molecules [20].”
Self-citationFan, G., Zha, J., Chen, S., et al. (2025) · Molecular Biomedicine · doi:10.1186/s43556-025-00369-1 · Cited by 3
“Additionally, PCSK9 influences the tumor microenvironment by promoting M2 macrophage polarization, further supporting tumor growth and metastasis [2, 4].”
Gantz, A., Kapelanski‐Lamoureux, A., Rada, M., Krzywoń, L., Tsamchoe, M., Tsatoumas, A., Petrillo, S. K., Seidah, N. G., Lazaris, A., & Metrakos, P. P. (2025) · FEBS Journal · doi:10.1111/febs.70348 · Cited by 5
“Moreover, PCSK9 inhibition potentiated the efficacy of anti-PD1 immunotherapy in mice [16].”
Markovska, A., Lommers, L. F., Bodelόn, A., Greve, P. F., der Zee, L. C. V. V., Mulder, M. T., Lennep, J. R. V., Zelcer, N., Schipper, H. S., & Boes, M. L. (2026) · iScience · doi:10.1016/j.isci.2026.114859 · Cited by 3
Sloot, R., Breskin, A., Colantonio, L. D., Allmon, A. G., Yu, Y., Sakhuja, S., Chen, L., Muntner, P., Brookhart, M. A., & Dhalwani, N. N. (2024) · Epidemiology · doi:10.1097/ede.0000000000001730 · Cited by 4
Association of lipid-lowering drugs with gut microbiota: A Mendelian randomization study
Shi, L., Liu, X., Li, E., Zhang, S., & Zhou, A. (2024) · Journal of clinical lipidology · doi:10.1016/j.jacl.2024.05.004 · Cited by 3
Self-citationBergeron, A., Chong, E. W., Joncas, F., Castonguay, C., Calon, F., Seidah, N. G., Blais, J., Robitaille, K., Bergeron, A., Fradet, V., et al. (2025) · Cancer Medicine · doi:10.1002/cam4.70587 · Cited by 3
PCSK9 is a passenger gene in head and neck cancer with minimal pathological influence
Kim, H., Park, D.-G., Choi, S., et al. (2025) · Archives of Oral Biology · doi:10.1016/j.archoralbio.2025.106302 · Cited by 3
Nuclear glycine decarboxylase suppresses STAT1-dependent MHC-I and promotes cancer immune evasion
Liu, R., Li, H.-F., Jiang, Q., Shi, J.-G., Ruan, Z.-L., Ren, P., Li, Y., Shu, H., & Li, S. (2025) · The EMBO Journal · doi:10.1038/s44318-025-00557-3 · Cited by 4
Saganty, R. S., Leiva, O., Hutchins, E., Stein-Merlob, A. F., & Yang, E. H. (2025) · Journal of the American Heart Association · doi:10.1161/jaha.125.042824 · Cited by 3
“82 Subsequent studies have shown synergism between PCSK9 inhibition and immune checkpoint inhibition, highlighting the potential utility of PCSK9 inhibitors in augmenting antitumor responses and counteracting the proatherogenic effects of ICIs.”
Lipoprotein compartmentalisation as a regulator of PCSK9 activity
Burnap, S. A., & Mayr, M. (2021) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2021.02.004 · Cited by 3
Yang, X., & Li, Q. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.916439 · Cited by 3
“Mechanistically, ICIs could competitively interact with immune checkpoint proteins to relieve cancermediated inhibition of T-cell function (Liu et al., 2020).”
BackgroundTACE/ADAM17 substrates associate with ACS (Ep-CAM, HB-EGF) and follow-up MACE (TNFR1 and TNFR2)
Chemaly, M., McAllister, R., Peace, A. J., Bjourson, A. J., Watterson, S., Parton, A., Clauss, M. A., & McGilligan, V. (2022) · Atherosclerosis Plus · doi:10.1016/j.athplu.2022.09.001 · Cited by 3
“It has been recently shown that inhibiting proprotein convertase subtilisin/kexin 9 (PCSK9), an important regulator of LDLR and the lipid metabolism, enhanced cancer therapy [39].”
BackgroundSome synergetic therapy strategies for overcoming hypoxia for photodynamic therapy of cancer
Chai, T., Li, Y., Cai, Y., Li, Y., Kenar, N., Lim, H. S., Temple, H., Chen, X., & Chen, W. (2023) · Journal of Cancer Metastasis and Treatment · doi:10.20517/2394-4722.2023.38 · Cited by 3
PCSK9 inhibition protects mice from food allergy
Lorant, V., Klein, M., Garçon, D., et al. (2024) · Translational research · doi:10.1016/j.trsl.2024.03.001 · Cited by 3
Lipid-lowering medications and risk of malignant melanoma: a Mendelian randomization study
Yang, B., Wang, H., Song, W., Feng, J., & Hou, S. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1408972 · Cited by 3
Cholesterol and Cholesterol-Lowering Medications in COVID-19—An Unresolved Matter
Grewal, T., Nguyen, M. K. L., & Buechler, C. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms251910489 · Cited by 5
“Furthermore, PCSK9 impaired the recycling of major histocompatibility complex class I (MHC-I) and favoured its lysosomal degradation [184] (Figure 4).”
BackgroundYu, X., Long, Y., Chen, B., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.04.11.439388 · Cited by 3
Circulating levels of PCSK9, ANGPTL3 and Lp(a) in stage III breast cancersPreprint
Chong, E. W., Joncas, F., Seidah, N. G., et al. (2022) · Research Square · doi:10.21203/rs.3.rs-1420016/v1 · Cited by 3
Iyer, K. A., Ivanov, J. M., Tenchov, R., Ralhan, K., Rodríguez, Y., Sasso, J. M., Scott, S. A., & Zhou, Q. A. (2023) · ChemRxiv · doi:10.26434/chemrxiv-2023-bpvfq · Cited by 3
Hamad, M. A., Muhammad, J. S., Rah, B., Hasan, H. A., Taneera, J., Soofi, A., & Awadallah, S. M. (2023) · Advanced Therapeutics · doi:10.1002/adtp.202300107 · Cited by 3
Rubio, Á. M., Oh, S., Roelandt, S., Stevens, D., Damme, E. V., Vermaelen, K. Y., Preter, K. D., & Everaert, C. (2024) · Scientific Reports · doi:10.1038/s41598-024-76982-x · Cited by 2
Prognostic implications of PCSK9 expression in HER2-positive breast cancer
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“The inhibition of PCSK9 may enhance tumor response to immune checkpoint therapy through a mechanism that is independent of PCSK9’s cholesterol-regulating functions (Liu et al. 2020).”
PCSK9 in Familial Hypercholesterolemia and Beyond
Abifadel, M. (2025) · JAMA Cardiology · doi:10.1001/jamacardio.2025.1408 · Cited by 2
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“In addition, PCSK9 regulates the sensitivity to immuno-therapy by modifying immune environment (31).”
PCSK9 Inhibitor and Potential Decreased Risk of Neoplasms, Especially in Females: A Meta-Analysis
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“Interestingly, the study [20] suggested that PCSK9 affects MHC I independently of its cholesterol-regulating function and that this effect may not be fully explained by cholesterol-dependent mechanisms [29], thereby preventing CD8 + T cells from recognizing and killing tumor cells.”
InfluentialConsensus guidance of immune checkpoint inhibitors in locally advanced rectal cancer
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“Besides, PCSK9 inhibitors potentiate tumor response to ICI-therapy by elevating MHC I expression on tumor cells, enhancing cytotoxic T-cell infiltration, without additional side effects [197].”
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Metabolic impact of extrahepatic PCSK9 modulation: Extrahepatic PCSK9 modulation
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“And PCSK9 antibodies synergize with anti-PD1 therapy in suppressing tumor growth in mouse models of cancer [32].”
BackgroundCurrent Understanding of PCSK9 and Its Relevance to Cancer Prognosis and Immune Therapy: A Review
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“In summary, we believe blocking PCSK9 would be a promising approach for improving cancer immune checkpoint therapy (23).”
BackgroundInfluentialPCSK9 V474I germline variant drives breast cancer metastasis
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“MHC-I expression can be enhanced by cytokines, and enzymes modulation within the cells, such as IFN-c and PCSK9 (Proprotein convertase subtilisin/kexin type 9), offering important targets for cancer immunotherapy [64,149].”
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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
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