Abstract
Converting checkpoint inhibitor (CPI)-resistant individuals to being responsive requires identifying suppressive mechanisms. We identify TREM2+ tumor-associated macrophages (TAMs) as being correlated with exhausted CD8+ tumor-infiltrating lymphocytes (TILs) in mouse syngeneic tumor models and human solid tumors of multiple histological types. Fc domain-enhanced anti-TREM2 monoclonal antibody (mAb) therapy promotes anti-tumor immunity by elimination and modulation of TAM populations, which leads to enhanced CD8+ TIL infiltration and effector function. TREM2+ TAMs are most enriched in individuals with ovarian cancer, where TREM2 expression corresponds to disease grade accompanied by worse recurrence-free survival. In an aggressive orthotopic ovarian cancer model, anti-TREM2 mAb therapy drives potent anti-tumor immunity. These results highlight TREM2 as a highly attractive target for immunotherapy modulation in individuals who are refractory to CPI therapy and likely have a TAM-rich tumor microenvironment.
Highlights
Checkpoint inhibitor (CPI) therapies elicit durable responses across a broad range of cancer indications, including metastatic melanoma, non-small cell lung cancer (NSCLC), and renal cancer (Wilky, 2019)
triggering receptor expressed on myeloid cells 2 (TREM2) expression is correlated with immune exhaustion and anti-PD-1 resistance in the mouse To identify genes that are significantly upregulated by tumor-associated macrophages (TAMs) in human tumor indications with a low response rate to anti-PD-1 treatment (Matulonis et al, 2019), we sorted CD45+ immune cells from a dissociated human ovarian tumor and performed single-cell RNA sequencing
Differential expression (DE) analysis between all populations identified in Figure 1A revealed genes that are enriched within TAMs and identified the cell surface molecule TREM2 as being highly expressed in TAMs compared with other immune populations in the ovarian tumor sample (Figure 1C; Table S1)
Summary
Checkpoint inhibitor (CPI) therapies elicit durable responses across a broad range of cancer indications, including metastatic melanoma, non-small cell lung cancer (NSCLC), and renal cancer (Wilky, 2019). The basis for CPI failure involves multiple mechanisms, including lack of tumor neoantigens (Jenkins et al, 2018; Le et al, 2017), failure to reverse T cell exhaustion (Miller et al, 2019; Pauken et al, 2016; Philip et al, 2017), and intra-tumoral presence of immunosuppressive immune cells, including tumor-associated macrophages (TAMs) (Dammeijer et al, 2017; Dannenmann et al, 2013; Jahchan et al, 2019). TAMs can directly (Peranzoni et al, 2018; Viitala et al, 2019; Wang et al, 2015) and indirectly suppress CD8+ tumor-infiltrating lymphocyte (TIL) function, drive immunosuppression through secretion of factors like interleukin-10 (IL-10) (Ruffell et al, 2014), and promote tumor cell proliferation and extravasation by supporting vascularization and development of extracellular matrices (ECMs) (Lin and Pollard, 2007; Penny et al, 2016; Qian et al, 2009). Reducing TAM frequency and/or modulating TAM function is a promising strategy to convert CPIresistant individuals into CPI-sensitive individuals
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