Immunosuppressive TREM2(+) macrophages are associated with undesirable prognosis and responses to anti-PD-1 immunotherapy in non-small cell lung cancer

Zhang, Hongyu; Liu, Zilong; Wen, Haoyu; Guo, Yifan; Xu, Fan; Zhu, Qinqing; Yuan, Wei; Luo, Rongkui; Chen, Lu; Liu, Ronghua; Gu, Jie; Ge, Di

doi:10.1007/s00262-022-03173-w

Cited by 53 publications

(57 citation statements)

References 44 publications

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“…Moreover, patients with progressive disease upon anti-PD-1 therapy showed a higher proportion of TREM2 + cells compared to patients with stable disease or partial response. This supports the potential prognostic value of TREM2 in NSCLC patients, as well as the relevance of TREM2 targeting in anti-PD-1 non-responders [60]. Overall, TREM2 + macrophages were shown to be accumulated in NSCLC tumors and associated with an immunosuppressive LAM-like signature, as well as poor patient outcome.…”

Section: Lung Adenocarcinomasupporting

confidence: 70%

“…This indicates that targeted therapy promotes TAM modulation, but in this specific context, namely type of treatment and advanced stage of disease, TREM2 + TAMs were not associated with a favorable response [59]. A different study analyzed a large dataset of NSCLC patients, and TREM2 + TAMs were shown to be enriched for APOE, APOC1, SPP1, C1QB-C, APOC2, and MARCO genes, as compared to TREM2 -TAMs [60]. Moreover, TREM2 + TAMs expressed higher levels of immunosuppressive markers such as CD206, ARG-1, and IL-10 by flow cytometry.…”

Section: Lung Adenocarcinomamentioning

confidence: 99%

“…CD8 T cells in tumors with high TREM2 + TAMs had a diminished production of effector molecules, such as Perforin (PRF1) and TNF-a. Using NSCLC tissue microarrays, it was noted that higher TREM2 expression positively correlated with advanced tumor stages, shortened overall survival, and recurrence-free survival [60]. Moreover, patients with progressive disease upon anti-PD-1 therapy showed a higher proportion of TREM2 + cells compared to patients with stable disease or partial response.…”

Section: Lung Adenocarcinomamentioning

confidence: 99%

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Exploring the Impact of TREM2 in Tumor-Associated Macrophages

2022

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Tumor-associated macrophages (TAMs) represent a key component of the tumor microenvironment and are generally associated with immunosuppression and poor prognosis. TREM2 is a transmembrane receptor of the immunoglobulin superfamily expressed in myeloid cells. TREM2 has been extensively studied in microglia and neurodegenerative diseases and recently emerged as a marker of pro-tumorigenic macrophages. The accumulation of TREM2-expressing TAMs was reported across numerous cancer patients and tumor models. TREM2 genetic blockade or TREM2 targeting with antibodies resulted in improved tumor control, enhanced response to anti-PD1, and significant changes in the tumor immune landscape. Preclinical studies paved the way for an ongoing clinical trial with a TREM2 depleting antibody and inspired further exploration of TREM2 targeting therapies. Here, we review the current knowledge about the impact of TREM2 in cancer, with an emphasis on the TREM2+ macrophage signature across different cancer types, the contribution of TREM2 to TAM phenotype and function, and the promising effects of TREM2 modulation.

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Section: Lung Adenocarcinomasupporting

confidence: 70%

Section: Lung Adenocarcinomamentioning

confidence: 99%

Section: Lung Adenocarcinomamentioning

confidence: 99%

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Exploring the Impact of TREM2 in Tumor-Associated Macrophages

2022

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“…In complement to this study, a TREM2-expressing macrophage subpopulation in HCC patient tissues were reported to resemble hepatic LAMs with upregulation of immunosuppressive pathways such as Treg recruitment and angiogenesis stimulation (27). TREM2 + TAMs in non-small cell lung cancer (NSCLC) patient tissues were also enriched for fatty acid metabolism and protumorigenic pathways (33).…”

Section: Trem2 Expression and Functions Within The Immune Cell Popula...mentioning

confidence: 73%

The therapeutic potential of TREM2 in cancer

2022

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Cancer continues to be a substantial health concern and a leading cause of death in the United States and around the world. Therefore, it is important to continue to explore the potential of novel therapeutic targets and combinatorial therapies. Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor of the immunoglobulin superfamily that associates with DNAX activation protein (DAP) 12 and DAP10 to propagate signals within the cell. TREM2 has primarily been recognized for its expression on cells in the monocyte-macrophage lineage, with the majority of work focusing on microglial function in Alzheimer’s Disease. However, expansion of TREM2 research into the field of cancer has revealed that epithelial tumor cells as well as intratumoral macrophages and myeloid regulatory cells also express TREM2. In this review, we discuss evidence that TREM2 contributes to tumor suppressing or oncogenic activity when expressed by epithelial tumor cells. In addition, we discuss the immunosuppressive role of TREM2-expressing intratumoral macrophages, and the therapeutic potential of targeting TREM2 in combination with immune checkpoint therapy. Overall, the literature reveals TREM2 could be considered a novel therapeutic target for certain types of cancer.

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“…As accumulating evidence has revealed a role of TREM2 in tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), we analyzed the expression of TREM2 in the eight clusters and found it to be high in cluster 1, cluster 2 and cluster 4 (Figure 3E), which were all derived from cancer tissues. TREM2 has been linked to poor prognosis and is a vital in inducing immunosuppression in the TME (32)(33)(34)(35)(36). To further study the clinical value of TREM2, we divided 360 HCC patients from the TCGA LIHC cohort into two groups according to the expression level of TREM2.…”

Section: Macrophages Are Related To the Immunosuppressive Environment...mentioning

confidence: 99%

Immunosuppressive landscape in hepatocellular carcinoma revealed by single-cell sequencing

et al. 2022

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Background/AimsHepatocellular carcinoma (HCC), accounting for 75-85% of primary liver cancer cases, is the third leading cause of cancer-related death worldwide. The purpose of this research was to examine the tumor immune microenvironment (TIME) in HCC.MethodsWe investigated the HCC TIME by integrated analysis of single-cell and bulk-tissue sequencing data to reveal the landscape of major immune cell types.ResultsRegulatory T(Treg) cells were found to be specifically distributed in the TIME of HCC. Several immune checkpoints, including TNFRSF4, TIGIT and CTLA4, were found to be uniquely overexpressed in Treg cells, and the glycolysis/gluconeogenesis pathway was enriched in Treg cells. We also discovered the presence of two NK-cell subsets with different cytotoxic capacities, one in an activated state with antitumor effects and another with an exhausted status. In addition, memory B cells in HCC were found to exist in a unique state, with high proliferation, low differentiation, and low activity, which was induced by overexpression of PRAP1 and activation of the MIF-CD74 axis.ConclusionsWe revealed the TIME landscape in HCC, highlighting the heterogeneity of major immune cell types and their potential mechanisms in the formation of an immunosuppressive environment. Hence, blocking the formation of the TIME could be a useful therapeutic strategy for HCC.

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Immunosuppressive TREM2(+) macrophages are associated with undesirable prognosis and responses to anti-PD-1 immunotherapy in non-small cell lung cancer

Cited by 53 publications

References 44 publications

Exploring the Impact of TREM2 in Tumor-Associated Macrophages

Exploring the Impact of TREM2 in Tumor-Associated Macrophages

The therapeutic potential of TREM2 in cancer

Immunosuppressive landscape in hepatocellular carcinoma revealed by single-cell sequencing

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