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. 2021 Oct 19;37(3):109844.
doi: 10.1016/j.celrep.2021.109844.

Targeting TREM2 on tumor-associated macrophages enhances immunotherapy

Mikhail Binnewies  1 , Joshua L Pollack  1 , Joshua Rudolph  1 , Subhadra Dash  1 , Marwan Abushawish  1 , Tian Lee  1 , Nadine S Jahchan  1 , Pamela Canaday  1 , Erick Lu  1 , Manith Norng  1 , Shilpa Mankikar  1 , Victoria M Liu  1 , Xiaoyan Du  1 , Amanda Chen  1 , Ranna Mehta  1 , Rachael Palmer  1 , Vladislava Juric  1 , Linda Liang  1 , Kevin P Baker  2 , Leonard Reyno  1 , Matthew F Krummel  3 , Michel Streuli  1 , Venkataraman Sriram  4
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Free article

Targeting TREM2 on tumor-associated macrophages enhances immunotherapy

Mikhail Binnewies et al. Cell Rep. .
Free article

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.

Trial registration: ClinicalTrials.gov NCT04691375.

Keywords: TAM; TREM2; afucosylation; checkpoint; exhaustion; glycoengineering; immunosuppression; immunotherapy; microenvironment; tumor-associated macrophages.

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Conflict of interest statement

Declaration of interests M.F.K. is a founder and shareholder in Pionyr Immunotherapeutics. M.B., M.A., T.L., E.L., P.C., V.M.L., A.C., M.S., and V.S. are shareholders and former employees of Pionyr Immunotherapeutics. S.D., J.L.P., J.R., N.S.J., M.N., S.M., X.D., R.M., R.P., V.J., L.L., L.R., and K.P.B. are current employees of Pionyr Immunotherapeutics. M.S. and V.S. are inventors on US patent 10,508,148 describing anti-TREM2 antibodies. M.F.K., J.L.P., and M.B. are inventors on US patent 10,428,143 describing relevant claims.

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