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

In the paper

“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).”

What the sources say

• Partly supported

  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)

  cites Peng et al., 2010 sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites Ulland et al., 2017 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Supported

  The Results section, under “Pro-fibrogenic phenotype of scar-associated macrophages,” states that TREM2+CD9+ macrophages derive from recruited circulating monocytes and have a pro-fibrogenic phenotype. The Results also report that these cells expand in cirrhotic livers and promote collagen expression by hepatic stellate cells. Page numbers are not provided in the supplied passages. (LLM, conf=0.94)

  cites Ramachandran et al., 2019 source

In the paper

“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).”

What the sources say

• Supported

  The Results section on adipose tissue macrophage remodeling reports that, after high-fat-diet feeding, Trem2-deficient mice failed to accumulate LAMs. The Results section on metabolic homeostasis reports adipocyte hypertrophy, glucose intolerance, and other metabolic abnormalities in those mice; the Discussion says Trem2-driven LAM formation prevents adipocyte hypertrophy and loss of systemic lipid homeostasis under obese conditions. (LLM, conf=0.94)

  cites Jaitin et al., 2019 source

In the paper

“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.”

What the sources say

• Supported

  The Results section, under “Paired immune cell mapping reveals a distinct macrophage signature in lung adenocarcinoma,” identifies TREM2 as up-regulated in a tumor-associated macrophage cluster. This supports the cited claim that TREM2+ macrophages have been reported in tumors; the sentence’s separate statement about their impact is not attributed to this source. (LLM, conf=0.93)

  cites Lavin et al., 2017 source
• Supported

  The Discussion (page not provided) reports TREM2 among the genes upregulated during the monocyte-to-M2 macrophage transition within the intratumoral myeloid population. This supports the cited claim that TREM2+ macrophages have been reported in tumors. (LLM, conf=0.93)

  cites Song et al., 2019 source

In the paper

“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).”

What the sources say

• Partly supported

  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)

  cites Peng et al., 2010 sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites Ulland et al., 2017 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Supported

  The Results section reports higher MITF expression in the placental HLA-DRhigh myeloid subset, describes MITF as involved in lysosomal biogenesis, and characterizes that subset as having tolerogenic potential. The citation supports the description of MITF and the placental subset; the sentence does not attribute its tumor-macrophage observations to Costa et al. (LLM, conf=0.90)

  cites Costa et al., 2017 source

In the paper

“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).”

What the sources say

• Partly supported

  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)

  cites Peng et al., 2010 sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites Ulland et al., 2017 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Hibbs et al., 1987 source
• ?Could not verify

  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)

  cites Murray et al., 2014 sourceExperimental — accuracy not yet measured
• ?Not matched

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

  cites Stuehr and Nathan, 1989

In the paper

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

In the paper

“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.”

In the paper

“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.”

In the paper

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

In the paper

“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).”

In the paper

“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.”

In the paper

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

In the paper

“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).”

In the paper

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

In the paper

“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.”

In the paper

“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).”

In the paper

“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).”

In the paper

“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.”

In the paper

“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.”

In the paper

“MCA/1956 grew progressively in WT mice, but was consistently attenuated in Trem2−/− mice (Figures 1A and 1B).”

In the paper

“In atherosclerosis, TREM2+ macrophages are enriched in atherosclerotic lesions and specialize in lipid catabolism (Cochain et al., 2018).”

What the sources say

• ?Not checked — no full text of the sourcecites Cochain et al., 2018 source

In the paper

“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.”

In the paper

“Thus, TREM2 might be targeted to modify tumor myeloid infiltrates and augment checkpoint immunotherapy.”

In the paper

“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.”

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Ulland and Colonna, 2018 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Wang et al., 2019 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Ulland and Colonna, 2018 source

In the paper

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

In the paper

“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).”

What the sources say

• ?Not matched

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

  cites Wu et al., 2015

In the paper

“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.”

In the paper

“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.”

In the paper

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

In the paper

“Mice from different genotypes were cohoused from birth and separated during the experiment (the day of tumor injection).”

In the paper

“our extensive pathology study of human tumors suggests that TREM2 may be a particularly attractive therapeutic target”

In the paper

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

In the paper

“Mice within experiments were age and sex matched.”