Binnewies et al. showed TREM2+ TAM enrichment in samples from several human solid tumor types and syngeneic mouse tumor models. This profile correlated with anti-PD-1 resistance and an increased frequency of exhausted CD8+ TILs, and high TREM2 expression paralleled worse recurrence-free survival in patients with ovarian cancer. Treating mice with an afucosylated anti-TREM2 antibody selectively reduced M2-like TAMs, skewed TAMs toward a proinflammatory phenotype, enhanced CD8+ TIL infiltration and activity, potentiated anti-PD-1 effects to induce immune memory, and promoted antitumor activity in an aggressive orthotopic ovarian cancer mouse model.
Contributed by Paula Hochman
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.
Author Info: (1) Pionyr Immunotherapeutics, South San Francisco, CA 94080, USA. (2) Pionyr Immunotherapeutics, South San Francisco, CA 94080, USA. (3) Pionyr Immunotherapeutics, South San Franc
Author Info: (1) Pionyr Immunotherapeutics, South San Francisco, CA 94080, USA. (2) Pionyr Immunotherapeutics, South San Francisco, CA 94080, USA. (3) Pionyr Immunotherapeutics, South San Francisco, CA 94080, USA. (4) Pionyr Immunotherapeutics, South San Francisco, CA 94080, USA. (5) Pionyr Immunotherapeutics, South San Francisco, CA 94080, USA. (6) Pionyr Immunotherapeutics, South San Francisco, CA 94080, USA. (7) Pionyr Immunotherapeutics, South San Francisco, CA 94080, USA. (8) Pionyr Immunotherapeutics, South San Francisco, CA 94080, USA. (9) Pionyr Immunotherapeutics, South San Francisco, CA 94080, USA. (10) Pionyr Immunotherapeutics, South San Francisco, CA 94080, USA. (11) Pionyr Immunotherapeutics, South San Francisco, CA 94080, USA. (12) Pionyr Immunotherapeutics, South San Francisco, CA 94080, USA. (13) Pionyr Immunotherapeutics, South San Francisco, CA 94080, USA. (14) Pionyr Immunotherapeutics, South San Francisco, CA 94080, USA. (15) Pionyr Immunotherapeutics, South San Francisco, CA 94080, USA. (16) Pionyr Immunotherapeutics, South San Francisco, CA 94080, USA. (17) Pionyr Immunotherapeutics, South San Francisco, CA 94080, USA. (18) Pionyr Immunotherapeutics, South San Francisco, CA 94080, USA. (19) Pionyr Immunotherapeutics, South San Francisco, CA 94080, USA. Electronic address: kbaker@pionyrtx.com. (20) Pionyr Immunotherapeutics, South San Francisco, CA 94080, USA. (21) Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: matthew.krummel@ucsf.edu. (22) Pionyr Immunotherapeutics, South San Francisco, CA 94080, USA. (23) Pionyr Immunotherapeutics, South San Francisco, CA 94080, USA. Electronic address: vesriram@gmail.com.
