Targeting TREM2 on tumor-associated macrophages enhances immunotherapy

• Published in: Cell reports (Cambridge) 2021-10, Vol.37 (3), p.109844-109844, Article 109844
• Main Authors: Binnewies, Mikhail, Pollack, Joshua L., Rudolph, Joshua, Dash, Subhadra, Abushawish, Marwan, Lee, Tian, Jahchan, Nadine S., Canaday, Pamela, Lu, Erick, Norng, Manith, Mankikar, Shilpa, Liu, Victoria M., Du, Xiaoyan, Chen, Amanda, Mehta, Ranna, Palmer, Rachael, Juric, Vladislava, Liang, Linda, Baker, Kevin P., Reyno, Leonard, Krummel, Matthew F., Streuli, Michel, Sriram, Venkataraman
• Format: Article
• Language: English
• Subjects: afucosylation; Animals; Antineoplastic Agents, Immunological - pharmacology; Antineoplastic Combined Chemotherapy Protocols - pharmacology; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Line, Tumor; checkpoint; Coculture Techniques; Drug Resistance, Neoplasm; exhaustion; Female; glycoengineering; HEK293 Cells; Humans; Immune Checkpoint Inhibitors - pharmacology; immunosuppression; immunotherapy; Lymphocyte Activation - drug effects; Lymphocytes, Tumor-Infiltrating - drug effects; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; microenvironment; Neoplasms - drug therapy; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - pathology; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - immunology; Programmed Cell Death 1 Receptor - metabolism; Receptors, Immunologic - antagonists & inhibitors; Receptors, Immunologic - metabolism; Signal Transduction; TAM; TREM2; Tumor Cells, Cultured; Tumor Microenvironment; tumor-associated macrophages; Tumor-Associated Macrophages - drug effects; Tumor-Associated Macrophages - immunology; Tumor-Associated Macrophages - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109844

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. [Display omitted] •TAM-expressed TREM2 is associated with T cell exhaustion and anti-PD-1 resistance•Effector-enhanced anti-TREM2 antibody treatment drives anti-tumor immunity•TAM abundance and suppression are reduced following anti-TREM2 therapy•Anti-TREM2 therapy potentiates T cell activation and response to anti-PD-1 treatment Binnewies et al. show that TREM2-expressing tumor-associated macrophages (TAMs) are critical mediators of immune suppression in the tumor microenvironment (TME) and correlate with T cell exhaustion in human cancer. Effector-enhanced anti-TREM2 antibody treatment alters the abundance and phenotype of TAMs in the TME and sensitizes the response to anti-PD-1 therapy.