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Cited by 657Cancer Immunotherapy and BiomarkersImmune cells in cancerPhagocytosis and Immune Regulation

TREM2 Modulation Remodels the Tumor Myeloid Landscape Enhancing Anti-PD-1 Immunotherapy

Open access
Molgora, Martina, Esaulova, Ekaterina, Vermi, William, Hou, Jinchao, Chen, Yun, Luo, Jingqin, Brioschi, Simone, Bugatti, Mattia +13 more·2020·Cell
DOI 10.1016/j.cell.2020.07.013PMC PMC7485282
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Abstract

SUMMARY Checkpoint immunotherapy unleashes T cell control of tumors, but is undermined by immunosuppressive myeloid cells. TREM2 is a myeloid receptor that transmits intracellular signals that sustain microglial responses during Alzheimer’s disease. TREM2 is also expressed by tumor-infiltrating macrophages. Here, we found that Trem2−/− mice are more resistant to growth of various cancers than wild-type mice and are more responsive to anti-PD-1 immunotherapy. Furthermore, treatment with anti-TREM2 mAb curbed tumor growth and fostered regression when combined with anti-PD-1. scRNA-seq revealed that both TREM2 deletion and anti-TREM2 are associated with scant MRC1+ and CX3CR1+ macrophages in the tumor infiltrate, paralleled by expansion of myeloid subsets expressing immunostimulatory molecules that promote improved T cell responses. TREM2 was expressed in tumor macrophages in over 200 human cancer cases and inversely correlated with prolonged survival for two types of cancer. Thus, TREM2 might be targeted to modify tumor myeloid infiltrates and augment checkpoint immunotherapy.

AI snapshot

Written from the paper’s full text.

TL;DR

TREM2 deficiency or anti-TREM2 antibody treatment restricts tumor growth and strongly enhances anti-PD-1 immunotherapy in mouse sarcoma and colorectal cancer models. TREM2 marks tumor-infiltrating macrophages in over 200 human cancers and correlates with worse survival in colorectal carcinoma and triple-negative breast cancer.

Key findings

  • Trem2−/− mice were more resistant than WT mice to MCA/1956 sarcoma, MC38 colorectal cancer, and PyMT mammary tumors; with suboptimal anti-PD-1 started on day 8, 40% of WT mice rejected MCA/1956 versus 100% of Trem2−/− mice, and all Trem2−/− mice controlled MC38 growth versus only a few WT mice.
  • Anti-TREM2 mAb 178 alone gave significant but incomplete tumor control, while anti-TREM2 plus suboptimal anti-PD-1 conferred complete tumor control in all mice tested; anti-TREM2 treatment attenuated tumor growth more than Trem2 deficiency, and did not further attenuate growth in Trem2−/− mice.
  • scRNA-seq showed that TREM2 deletion and anti-TREM2 treatment reduced MRC1+ and CX3CR1+ macrophage subsets and expanded immunostimulatory myeloid subsets; anti-TREM2 induced de novo Nos2-Macs-t and reduced Mrc1-Macs-t, Cycling-Macs-t, and Macs1-t.
  • TREM2 was expressed in tumor macrophages in over 200 human cancer cases, including 75% of carcinomas in a 126-sample tissue microarray and virtually all 99 whole tumor sections; TREM2 expression inversely correlated with overall survival in CRC and with overall and relapse-free survival in TNBC.

Methods

  • Mouse tumor models included MCA/1956 sarcoma, MC38 colorectal cancer, and PyMT mammary tumors in WT and Trem2−/− mice, with anti-PD-1, Fc-mutated anti-TREM2 mAb 178, control antibodies, CD4/CD8 depletion, flow cytometry, immunofluorescence, and ex vivo T cell cytokine analysis.
  • scRNA-seq was performed on live CD45+ cells sorted from MCA/1956 tumors at day 10; genotype comparison averaged 19,758 cells with 13,545 UMI per cell, and antibody-treatment comparison averaged 2,726 cells per condition with 14,622 UMI per cell, analyzed with Seurat and UMAP.
  • Human analyses used FFPE tissues including a multi-tumor tissue microarray of 126 samples, primary carcinomas (n = 99), tumor-draining lymph nodes (n = 33), and distant metastases (n = 12), plus TCGA survival and correlation analyses.

Limitations

  • The paper states that mechanisms by which TREM2 deficiency and anti-TREM2 treatment impact tumor macrophages remain unclear, that future biochemical experiments are needed, and that variability was noted in T cell expansion and effector function between Trem2−/− and anti-TREM2-treated mice.
  • The paper states that the anti-PD-1 regimen used was suboptimal and initiated late, and that TREM2’s survival association was not significant in other tumor types, suggesting context specificity.
  • Evident from the text: several experiments were performed once or with small n, scRNA-seq used n = 2 per condition in one experiment, and human evidence is largely IHC/correlation without functional validation; combined anti-TREM2 plus anti-PD-1 cleared tumors, so no infiltrate could be analyzed in that group.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.cell.2020.07.013

Cites

66 of 66 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

15 of 25 cited sources checked · 5 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Trem2−/− macrophages present antigens to T cells more effectively than WT macrophages in vitro.

    “Trem2−/− macrophages were shown to present antigens to T cells more effectively than WT macrophages in vitro (Ito and Hamerman, 2012).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Ito and Hamerman, 2012 source

      The Results section (“TREM-2 negatively regulates antigen-specific T cell proliferation by BMDCs”; page unavailable) reports that TREM-2-deficient bone-marrow-derived dendritic cells induced more antigen-specific T-cell division than WT dendritic cells in vitro. The cited experiment did not test macrophages, so the claim attributes the finding to the wrong cell type. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
  • Premisecitation

    TREM2 cooperates with CSF-1 in sustaining macrophage proliferation and survival.

    “We have previously shown that TREM2 cooperates with CSF-1 in sustaining macrophage proliferation and survival (Ulland et al., 2017).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Ulland et al., 2017 source

      The Results section on macrophage mTOR signaling shows that TREM2-deficient bone marrow-derived macrophages have impaired mTOR signaling and increased autophagy when CSF1 is limiting. The Discussion says TREM2-supported mTOR signaling promotes survival and proliferation in microglia, but the cited passages do not establish that TREM2 cooperates with CSF1 to sustain macrophage proliferation and survival. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • Premisecitation

    TREM2 is induced in human monocytes and mouse bone marrow cells upon exposure to GM-CSF and CSF-1.

    “We have previously shown that TREM2 is induced in human monocytes and mouse bone marrow cells upon exposure to GM-CSF and CSF-1 (Bouchon et al., 2001; Turnbull et al., 2006).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Bouchon et al., 2001 source

      The Results section on immature monocyte-derived dendritic cells reports high TREM-2 expression after human monocytes were cultured with GM-CSF and IL-4. It does not report induction in mouse bone marrow cells or by CSF-1; in fact, TREM-2 was undetectable in human monocyte-derived macrophages cultured with M-CSF. No page number is available in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Turnbull et al., 2006 source
  • Findingown data

    T cells and NK cells in Trem2−/− MCA tumors had heightened expression of activation markers such as IFNγ and PD-1 (Pdcd1).

    “We also re-clustered lymphoid cells, revealing heightened expression of activation markers, such as IFNγ and PD-1 (Pdcd1), by T cells and NK cells in Trem2−/− MCA tumors (Figures S2F–S2I).”
    Quote in the paperSubstantial claim
  • Findingown data

    TREM2 expression inversely correlated with overall survival and relapse in CRC and TNBC patients.

    “TREM2 expression inversely correlated with overall survival and relapse in these cancer patients.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 19
  • May combine two claims. 27

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    TREM2 is an activating receptor of the Ig-superfamily that binds lipids and transmits intracellular signals through the adaptor DAP12.

    “TREM2 is an activating receptor of the Ig-superfamily that binds lipids and transmits intracellular signals through the adaptor DAP12 (Peng et al., 2010; Ulland et al., 2017).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Peng et al., 2010 source

      The Introduction identifies TREM2 as an immunoglobulin-like, DAP12-associated receptor, and the Discussion describes signaling through the TREM2–DAP12 pathway. The Discussion says specific endogenous ligands for TREM2 were not yet known; this paper does not establish that TREM2 binds lipids. Page numbers are unavailable in our copy. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
    • cites Ulland et al., 2017 source

      The Introduction (page unavailable) says TREM2 recognizes phospholipids and transmits intracellular signals through DAP12 and DAP10; the Discussion describes it as an innate immune receptor involved in signaling. Our copy does not identify TREM2 as a member of the Ig-superfamily, so that part of the attributed description is unsupported. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In liver, a TREM2+CD9+ subset of macrophages that differentiate from circulating monocytes expands during liver cirrhosis and contributes to fibrosis.

    “In the liver, a TREM2+CD9+ subset of macrophages that differentiate from circulating monocytes expands during liver cirrhosis and contributes to fibrosis (Ramachandran et al., 2019).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Ramachandran et al., 2019 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In adipose tissue, TREM2 sustains a population of lipid-associated macrophages (LAMs) that prevent dysmetabolism engendered by a high-fat diet.

    “In the adipose tissue, TREM2 sustains the presence of a population of lipid-associated macrophages (LAMs) that prevent the dysmetabolism engendered by a high-fat diet (Jaitin et al., 2019).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Jaitin et al., 2019 source

  • Classified as probably not a substantial claim.

    Premisecitation

    TREM2+ macrophages have been reported in tumors.

    “TREM2+ macrophages have also been reported in tumors (Lavin et al., 2017; Song et al., 2019), but the impact of TREM2 in tumor immune responses has not been addressed.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Lavin et al., 2017 source
    • cites Song et al., 2019 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    DAP12 recruits Syk, initiating tyrosine phosphorylation that activates downstream mediators such as PLCγ2, PI-3K, Vav, mTOR, and MAPK, leading to cell activation.

    “DAP12 recruits the protein tyrosine kinase Syk, which initiates a cascade of tyrosine phosphorylation events that activate downstream mediators such as PLCγ2, PI-3K, Vav, mTOR, and MAPK, ultimately leading to cell activation (Peng et al., 2010; Ulland et al., 2017).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Peng et al., 2010 source

      The Discussion (page unavailable) describes a TREM2–DAP12 signaling complex containing Syk and PI3K p85, and reports activation of PLC-γ2, Vav3, and ERK1/2, a MAPK, in pathways involved in cell activation. It does not identify mTOR as a downstream mediator or establish the entire sequence as a Syk-initiated phosphorylation cascade. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Ulland et al., 2017 source

      The Introduction states that TREM2-associated DAP12 recruits Syk, while DAP10 recruits PI3-K. The Results link TREM2 signaling to PI3-K and mTOR, but the cited passages do not establish the claimed Syk-initiated tyrosine-phosphorylation cascade or identify PLCγ2, Vav, and MAPK as its downstream mediators. Page numbers are not available in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    TREM2+ tumor macrophages co-expressed CD68, CD163, CSF1R, and nuclear MAFB; foamy TREM2+ tumor macrophages also co-expressed MITF.

    “TREM2+ tumor macrophages co-expressed CD68, CD163, CSF1R, and nuclear MAFB; foamy TREM2+ tumor macrophages also co-expressed MITF, a transcription factor involved in lysosomal biogenesis that marks a regulatory myeloid subset of human placenta (Costa et al., 2017).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Costa et al., 2017 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    TREM2 signaling pathways include proliferation and survival, metabolism, migration and chemokine production.

    “TREM2-signaling pathways, which include not only proliferation and survival, but also metabolism, migration and chemokine production (Peng et al., 2010; Ulland et al., 2017).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Peng et al., 2010 source

      The Results section on SHIP1 and TREM2/DAP12 signaling reports survival signaling, and the Discussion proposes a link between DAP12 signaling and increased proliferation. The paper reports actin reorganization, but does not establish migration; the passages found do not address metabolism or chemokine production. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Ulland et al., 2017 source

      The Discussion (page unavailable) links TREM2 signaling to metabolism, survival, proliferation, and microglial clustering around plaques. Clustering may relate to migration, but the passages do not establish migration as a signaling outcome, and they do not support the claim about chemokine production. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    iNOS2 has been associated with immunostimulation and immunosuppression.

    “iNOS2, which has been associated with immunostimulation (Hibbs et al., 1987; Murray et al., 2014; Stuehr and Nathan, 1989), as well as immunosuppression (Shi et al., 2001).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Hibbs et al., 1987 source
    • cites Murray et al., 2014 source

      The Background to the problem (p. 4) discusses macrophage activation and arginine metabolism, but does not link iNOS2 to immunostimulation. Searches for iNOS, NOS2, and nitric oxide did not locate a passage in our copy making that association. In the citing sentence, immunosuppression is attributed to Shi et al. (2001), not to this source. (LLM, conf=0.71)

      Experimental — accuracy not yet measured
    • cites Stuehr and Nathan, 1989

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingown data

    All Trem2−/− mice controlled MC38 tumor growth as opposed to only a few WT mice under suboptimal anti-PD-1.

    “Indeed, all Trem2−/− mice controlled tumor growth as opposed to only a few WT mice (Figures 4D and 4E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both TREM2 deletion and anti-TREM2 are associated with scant MRC1+ and CX3CR1+ macrophages in the tumor infiltrate.

    “scRNA-seq revealed that both TREM2 deletion and anti-TREM2 are associated with scant MRC1+ and CX3CR1+ macrophages in the tumor infiltrate, paralleled by expansion of myeloid subsets expressing immunostimulatory molecules that promote improved T cell responses.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Upon depletion of CD8+ T cells, but not CD4+ T cells, tumor growth was no longer attenuated, but accelerated in Trem2−/− mice.

    “Upon depletion of CD8+ T cells (Figure 1E), but not CD4+ T cells (Figure S1C), tumor growth was no longer attenuated, but in fact accelerated in Trem2−/− mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TREM2 was expressed in all macrophage clusters, although at different levels, while absent in DCs and lymphoid cells.

    “Moreover, TREM2 was expressed in all macrophage clusters, although at different levels, while it was absent in DCs and lymphoid cells (Figure S2E).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Anti-TREM2 treatment augments IFNγ and TNFα production by intra-tumoral CD8+ and CD4+ T cells, respectively.

    “However, analysis of T cell cytokine production ex vivo indicated that anti-TREM2 treatment augments IFNγ and TNFα production by intra-tumoral CD8+ and CD4+ T cells, respectively (Figure 5E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Macs1-t declined, while Macs2-t expanded following anti-TREM2.

    “One of the macrophage subsets that recently immigrated into the tumor, Macs1-t, also declined, while the other one—Macs2-t—expanded, perhaps reflecting changes in the intratumoral differentiation of blood-derived monocytes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Both native and Fc mutated mAb 178 inhibited HDL-induced EGFP expression, indicating that mAb 178 blocks ligand binding to TREM2.

    “Both native and Fc mutated mAb 178 inhibited HDL-induced EGFP expression, indicating that mAb 178 blocks ligand binding to TREM2 (Figure S3B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At a later time point (24 days), anti-TREM2 alone reduced representation of Ly6ClowMHCII− cells, along with subsets expressing CD206, CD63, and CD9, while total macrophages were unchanged.

    “At a later time point (24 days after tumor injection), in parallel with a considerable shrinkage of the tumor volume, anti-TREM2 alone showed a significant impact on the myeloid compartment: while the total number of macrophages was unchanged, the representation of Ly6ClowMHCII− cells, along with subsets expressing CD206, CD63, and CD9, was reduced (Figure S3E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Following suboptimal anti-PD-1 starting day 8, only 40% of WT mice rejected tumor, whereas 100% of Trem2−/− mice did.

    “Following this treatment protocol, only 40% of WT mice rejected the tumor, whereas 100% of Trem2−/− mice did (Figures 4B and 4C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both TREM2 deletion and anti-TREM2 are associated with expansion of myeloid subsets expressing immunostimulatory molecules.

    “scRNA-seq revealed that both TREM2 deletion and anti-TREM2 are associated with scant MRC1+ and CX3CR1+ macrophages in the tumor infiltrate, paralleled by expansion of myeloid subsets expressing immunostimulatory molecules that promote improved T cell responses.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CX3CR1-Macs-g, Mrc1-Macs-g, Cycling-Macs-g, and Macs3-g were relatively meagerly represented in Trem2−/− tumors, whereas the Macs1-g cluster predominated.

    “We noticed that CX3CR1-Macs-g, Mrc1-Macs-g, Cycling-Macs-g, and Macs3-g were relatively meagerly represented in Trem2−/− tumors, whereas the Macs1-g cluster predominated (Figures S2B–S2D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CD8+ T cells were increased in Trem2−/− mice with or without anti-PD-1, as were PD-1+ CD8 T cells.

    “CD8+ T cells were increased in Trem2−/− mice with or without anti-PD-1, as were PD-1+ CD8 T cells, corroborating our initial results (see Figure 1C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The representation of TREM2+ macrophages was not affected by mAb 178, indicating no antibody-mediated depletion.

    “The representation of TREM2+ macrophages was not affected by mAb 178 (Figure S3C), indicating no antibody-mediated depletion, consistent with lack of effector function in the mutated Fc fragment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Other types of human tumors also showed a correlation between TREM2 and macrophage signature genes, but the association of TREM2 expression with patient overall or relapse-free survival was not significant.

    “Other types of human tumors also showed a correlation between TREM2 and macrophage signature genes, but the association of TREM2 expression with patient overall or relapse-free survival was not significant (data not shown), suggesting that TREM2 impact on tumor-infiltrating macrophages and tumor immune responses might be context specific.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    MCA/1956 grew progressively in WT mice but was consistently attenuated in Trem2−/− mice.

    “MCA/1956 grew progressively in WT mice, but was consistently attenuated in Trem2−/− mice (Figures 1A and 1B).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Many macrophage subsets infiltrating MCA/1956 tumors express TREM2.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In atherosclerosis, TREM2+ macrophages are enriched in atherosclerotic lesions and specialize in lipid catabolism.

    “In atherosclerosis, TREM2+ macrophages are enriched in atherosclerotic lesions and specialize in lipid catabolism (Cochain et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Cochain et al., 2018 source

  • May combine two claims.

    Interpretationown data

    Anti-TREM2 treatment induces a complex remodeling of the myeloid compartment that drives the appearance of Nos2-Macs-t and a parallel decline of Mrc1-Macs-t, Cycling-Macs-t, and Macs1-t recent immigrants.

    “We conclude that anti-TREM2 treatment induces a complex remodeling of the myeloid compartment that drives the appearance of Nos2-Macs-t and a parallel decline of Mrc1-Macs-t, Cycling-Macs-t, and Macs1-t recent immigrants.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    TREM2 might be targeted to modify tumor myeloid infiltrates and augment checkpoint immunotherapy.

    “Thus, TREM2 might be targeted to modify tumor myeloid infiltrates and augment checkpoint immunotherapy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Treatment of Trem2−/− mice with anti-TREM2 mAb did not further attenuate tumor growth, demonstrating that anti-TREM2 treatment has no off-target effects.

    “Yet, treatment of Trem2−/− mice with the anti-TREM2 mAb did not further attenuate tumor growth, demonstrating that anti-TREM2 treatment has no off-target effects.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    TREM2 is cleaved from the cell surface by metalloproteases and released as soluble TREM2 (sTREM2).

    “Although TREM2 is expressed on the cell surface, it is cleaved from the cell surface by metalloproteases and released as soluble TREM2 (sTREM2) (Ulland and Colonna, 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ulland and Colonna, 2018 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In skin, TREM2+ dermal macrophages secrete oncostatin M, which inhibits hair growth by maintaining hair follicle stem cells quiescent.

    “In the skin, TREM2+ dermal macrophages secrete oncostatin M, which inhibits hair growth by maintaining hair follicle stem cells in a quiescent state (Wang et al., 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wang et al., 2019 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    TREM2 sustains microglial responses to neurodegenerative pathologies such as Alzheimer's disease.

    “TREM2 has been extensively studied in microglia for its capacity to sustain microglial responses to neurodegenerative pathologies such as Alzheimer’s disease (Ulland and Colonna, 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ulland and Colonna, 2018 source

  • Classified as probably not a substantial claim.

    Interpretationnone given

    Anti-TREM2 treatment provides a novel therapeutic approach that broadens the armamentarium for myeloid cell targeting in tumors.

    “The anti-TREM2 treatment presented here provides a novel therapeutic approach that broadens the armamentarium for myeloid cell targeting in tumors.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    During lung acute viral infection, TREM2+ macrophages release sTREM2, which inhibits apoptosis of macrophages, causing feed-forward expansion of lung macrophages that converts acute infection into chronic inflammatory disease.

    “During lung acute viral infection, TREM2+ macrophages release sTREM2, which inhibits apoptosis of macrophages, causing a feed-forward expansion of lung macrophages that converts acute infection into a chronic inflammatory disease (Wu et al., 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wu et al., 2015

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationown data

    Constitutive lack of TREM2 or anti-TREM2 treatment curbs tumor growth and leads to complete tumor regression when associated with suboptimal PD-1 immunotherapy.

    “This study demonstrates that constitutive lack of TREM2 or anti-TREM2 treatment curbs tumor growth and leads to complete tumor regression when associated with suboptimal PD-1 immunotherapy.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Cells identified as doublets or multiplets based on gene expression signatures were filtered out.

    “Cells identified as doublets or mutliplets based on gene expression signatures, when more than one cell population-specific marker gene was highly expressed in one cell, were filtered out.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Cells with mitochondrial content greater than 12.5% and with less than 1100 genes were removed.

    “Cells with mitochondrial content greater than 12.5% and with less than 1100 genes were removed.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Mice from different genotypes were cohoused from birth and separated during the experiment.

    “Mice from different genotypes were cohoused from birth and separated during the experiment (the day of tumor injection).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationown data

    TREM2 may be a particularly attractive therapeutic target.

    “our extensive pathology study of human tumors suggests that TREM2 may be a particularly attractive therapeutic target”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All animals were backcrossed until at least > 98% C57BL/6J confirmed by genotype wide microsatellite typing.

    “All animals were backcrossed until at least > 98% C57BL/6J confirmed by genotype wide microsatellite typing.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Mice within experiments were age and sex matched.

    “Mice within experiments were age and sex matched.”
    Quote in the paperNot a substantial claim
39 of 39

  • The paper relies on this without support.

    Many macrophage subsets infiltrating MCA/1956 tumors express TREM2.

    “These tumors have recently been shown to be infiltrated by a variety of macrophage subsets (Gubin et al., 2018), many of which express TREM2 (unpublished data).”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • A mouse TREM2 blocking antibody with Fc domain mutations to prevent Fc receptor and complement recognition was developed and shown to block binding of TREM2 and its high-avidity ligands.

    “In our previous study, a mouse TREM2 blocking antibody, with mutations in the Fc domain to prevent its recognition by the Fc receptor and complement, was developed and shown to block the binding of TREM2 and its high-avidity ligands38.”

    From TREM2 promotes lung fibrosis via controlling alveolar macrophage survival and pro-fibrotic activity (2025) · cites this paper as [38]

    The Results section, “Anti-TREM2 Treatment Is Protective in the Sarcoma Model,” says the authors generated an Fc-mutated mouse anti-TREM2 antibody to prevent Fc-receptor and complement recognition. It reports that the antibody inhibited signaling induced by lipidated HDL, indicating blockade of ligand binding to TREM2. Our copy does not establish that it blocks high-avidity ligands as a class; the reported blocking experiment used HDL. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • TREM2+ macrophages are associated with failure of CPI targeting the PD-1/PD-L1 axis.

    “and are known to be associated with failure of CPI targeting the PD-1/PD-L1 axis.80,81”

    From Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy (2023) · cites this paper as [81]

    In Results, “TREM2 Deficiency Enhances Checkpoint Blockade” (page unavailable), suboptimal anti-PD-1 treatment led to tumor rejection in 40% of wild-type mice versus 100% of Trem2-deficient mice. This supports a role for TREM2 in reduced anti-PD-1 efficacy in the studied mouse models, but does not establish a general association between TREM2+ macrophages and failure of PD-1/PD-L1-targeting therapy, particularly in patients or with anti-PD-L1 treatment. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • CyC is associated with recruitment of immunosuppressive Trem2+ macrophages, which in turn promote failure of cancer immunotherapy.

    “we propose a model in which CyC is associated with recruitment of immunosuppressive Trem2+ macrophages,80,81 which in turn promote failure of cancer immunotherapy.”

    From Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy (2023) · cites this paper as [81]

    The Results sections on macrophage subsets and checkpoint blockade report TREM2-expressing tumor macrophages with immunosuppression-associated markers and improved anti-PD-1 responses when TREM2 is absent. They do not link CyC to recruitment of those macrophages. Page numbers are unavailable in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • High-confidence Trem2+ monocytes were identified by expression of known TREM2+ monocyte markers (TREM2, APOE, CSF1R) using gene-weighted density estimation in Nebulosa.

    “High-confidence Trem2+ monocytes were identified by expression of known TREM2+ monocyte markers (TREM2, APOE, CSF1R81,89), identified by gene-weighted density estimation implemented in the Nebulosa package for R.78”

    From Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy (2023) · cites this paper as [81]

    The Results section, “Trem2 Is Selectively Expressed in Human Tumor Macrophages” (page unavailable), reports that TREM2+ tumor macrophages co-express CSF1R. “TREM2 Correlates with Poor Disease Prognosis” reports a correlation between TREM2 and APOE expression in a colorectal-cancer cohort. These passages do not establish TREM2, APOE, and CSF1R together as markers of TREM2+ monocytes; the Nebulosa method is cited separately in the citing sentence. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • The TREM2 blocking antibody can specifically demonstrate the effect of receptor TREM2 blockade without confounding ADCC or ADCP in vivo.

    “This antibody is particularly useful because it can specifically demonstrate the effect of receptor TREM2 blockade without the confounding activity of antibody-dependent cellular cytotoxicity or antibody-dependent phagocytosis in vivo.”

    From TREM2 promotes lung fibrosis via controlling alveolar macrophage survival and pro-fibrotic activity (2025) · cites this paper as [38]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Self-check results appear here once an independent check has confirmed them.

Cited works that were retracted

Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.

  • Cites a retracted work: 10.1172/jci98769

    Info

    The cited work was retracted on 2022-03-15 (notice 10.1172/jci159825), not before this paper was published (2020-08).

    Cited work 10.1172/jci98769 · retracted 2022-03-15 · notice 10.1172/jci159825 · this paper published 2020-08

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Authors
Molgora, M., Esaulova, E., Vermi, W., Hou, J., Chen, Y., Luo, J., Brioschi, S., Bugatti, M., Omodei, A. S., Ricci, B., Fronick, C., Panda, S. K., Takeuchi, Y., Gubin, M. M., Faccio, R., Cella, M., Gilfillan, S., Unanue, E. R., Artyomov, M. N., Schreiber, R. D., & Colonna, M.
Affiliations
  • Washington University in St. Louis (US)
  • University of Brescia (IT)
  • The University of Texas MD Anderson Cancer Center (US)
Corresponding author
Colonna, Marco
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2020-08
Volume
182
Issue
4
Pages
886-900.e17
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2020.07.013
PMC
PMC7485282
OpenAlex
W3048665145
Semantic Scholar
f3e033b1cb47f2b00fc56e9c646a9bcdde754590
Cited by
656
References
65
Citations by year
2026: 117 · 2025: 124 · 2024: 127 · 2023: 116 · 2022: 97 · 2021: 63 · 2020: 11 · 2014: 1
FWCI
23.02
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
  • Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
Funders
National Institutes of Health
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
Keywords
TREM2, tumor-infiltrating macrophages, anti-PD-1 therapy, cancer immunotherapy, TREM2 knockout mice, CX3CR1+ macrophages, immunosuppressive myeloid cells, T cell response
MeSH terms
CX3C Chemokine Receptor 1, Animals, Antibodies, Monoclonal, Disease Models, Animal, Humans, Immunotherapy, Membrane Glycoproteins, Methylcholanthrene, Mice, Inbred C57BL, Neoplasms, Prognosis, Receptors, Immunologic, Lymphocytes, Tumor-Infiltrating, Mice, Knockout, Cell Line, Tumor, Mice, Tumor Microenvironment, 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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-19.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-19.

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