Targeting TREM2 on tumor-associated macrophages enhances immunotherapy

被引：262

作者：

Binnewies, Mikhail ^{[1
]}

Pollack, Joshua L. ^{[1
]}

Rudolph, Joshua ^{[1
]}

Dash, Subhadra ^{[1
]}

Abushawish, Marwan ^{[1
]}

Lee, Tian ^{[1
]}

Jahchan, Nadine S. ^{[1
]}

Canaday, Pamela ^{[1
]}

Lu, Erick ^{[1
]}

Norng, Manith ^{[1
]}

Mankikar, Shilpa ^{[1
]}

Liu, Victoria M. ^{[1
]}

Du, Xiaoyan ^{[1
]}

Chen, Amanda ^{[1
]}

Mehta, Ranna ^{[1
]}

Palmer, Rachael ^{[1
]}

Juric, Vladislava ^{[1
]}

Liang, Linda ^{[1
]}

Baker, Kevin P. ^{[1
]}

Reyno, Leonard ^{[1
]}

Krummel, Matthew F. ^{[2
]}

Streuli, Michel ^{[1
]}

Sriram, Venkataraman ^{[1
]}

机构：

[1] Pionyr Immunotherapeut, San Francisco, CA 94080 USA

[2] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA

来源：

CELL REPORTS | 2021年 / 37卷 / 03期

关键词：

ANTITUMOR-ACTIVITY; CANCER; EXPRESSION; ADENOCARCINOMA; INHIBITION; MECHANISMS; LANDSCAPE; ANTIGEN; SEQ;

D O I：

10.1016/j.celrep.2021.109844

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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.

引用

页数：24

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