Targetable TREM2⁺ Myeloid Cells Mediate Immunsuppression in Tumors

Immunosuppression mediated by cells such as myeloid-derived suppressor cells in the tumor microenvironment (TME) has been linked to poor outcomes in cancer and reduced response to immunotherapies. Recently, macrophages characterized by expression of the cell-surface receptor TREM2, which sometimes also exists as a soluble fragment, have been identified in tumors, but the significance of these cells is unclear. Complementary work by Katzenelenbogen, Sheban, Yalin, and colleagues and Molgora and colleagues converged on an important role for TREM2⁺ myeloid cells in immunosuppression in cancer. Katzenelenbogen, Sheban, Yalin, and colleages employed a novel approach that involved integrating single-cell RNA sequencing with profiling of intracellular protein activity (dubbed intracellular staining and sequencing, or INs-seq). Metabolic characterization of cells in the TME using INs-seq uncovered a TREM2⁺ subset of regulatory monocytes, and these cells were shown to mediate immunosuppression in a syngeneic mouse model of fibrosarcoma. In this mouse model, Trem2 deficiency blocked accumulation of these TREM2⁺ regulatory monocytes, leading to reduced numbers of dysfunctional CD8⁺ T cells and dampened tumor growth. Independently, Molgora and colleagues investigated whether TREM2 has immunomodulatory properties in cancer. In agreement with the findings of Katzenelenbogen, Sheban, Yalin, and colleagues, Molgora and colleagues found that Trem2 deficiency in mouse models of chemically induced sarcoma, colorectal cancer, and breast cancer slowed tumor growth and altered the immune-cell composition of the TME. Specifically, the TME in Trem2-deficient tumors had a different balance of macrophage subsets and increased numbers of CD8⁺ T cells. Notably, immune-checkpoint blockade with anti–PD-1 was more effective in Trem2-deficient mice, and administration of an Fc-muated monoclonal TREM2 antibody enhanced the antitumor efficacy of anti–PD-1 in wild-type mice. Demonstrating the potential clinical relevance of these findings, TREM2 expression was associated with reduced durations of overall survival and relapse-free survival in patients with colorectal carcinoma and triple-negative breast cancer. Together, these studies highlight the role of TREM2⁺ myeloid cells in mediating immunosuppression in the TME and present possible avenues to new therapies.

Katzenelenbogen Y, Sheban F, Yalin A, Yofe I, Svetlichnyy D, Jaitin DA, et al. Coupled scRNA-seq and intracellular protein activity reveal an immunosuppressive role of TREM2 in cancer. Cell 2020:182:872–85.

Molgora M, Esaulova E, Vermi W, Hou J, Chen Y, Luo J, et al. TREM2 modulation remodels the tumor myeloid landscape enhancing anti-PD-1 immunotherapy. Cell 2020;182:886–900.

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