Targeting TREM2 on tumor-associated macrophages enhances immunotherapy
Open accessAbstract
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.
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TREM2+ macrophages are associated with failure of CPI targeting the PD-1/PD-L1 axis.
“and are known to be associated with failure of CPI targeting the PD-1/PD-L1 axis.80,81”
From Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy (2023) · cites this paper as [80]
CyC is associated with recruitment of immunosuppressive Trem2+ macrophages, which in turn promote failure of cancer immunotherapy.
“we propose a model in which CyC is associated with recruitment of immunosuppressive Trem2+ macrophages,80,81 which in turn promote failure of cancer immunotherapy.”
From Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy (2023) · cites this paper as [80]
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Macrophages in health and disease
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- Authors
- Binnewies, M., Pollack, J. L., Rudolph, J., Dash, S., Abushawish, M., Lee, T., Jahchan, N. S., Canaday, P., Lu, E., Norng, M., Mankikar, S., Liu, V. M., Du, X., Chen, A., Mehta, R., Palmer, R., Juric, V., Liang, L., Baker, K. P., Reyno, L., Krummel, M. F., Streuli, M., & Sriram, V.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Baker, Kevin P.
- Krummel, Matthew F.
- Sriram, Venkataraman
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2021-10
- Volume
- 37
- Issue
- 3
- Pages
- 109844
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W3206564803
- Cited by
- 365
- References
- 10
- Citations by year
- 2026: 76 · 2025: 85 · 2024: 99 · 2023: 75 · 2022: 29 · 2021: 1
- FWCI
- 19.19
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- TREM2, tumor-associated macrophages, CD8+ T cell exhaustion, tumor-infiltrating lymphocytes, tumor microenvironment, ovarian cancer, immunotherapy, antitumor immunity
- MeSH terms
- Antineoplastic Agents, Immunological, Immune Checkpoint Inhibitors, Tumor-Associated Macrophages, Animals, Antineoplastic Combined Chemotherapy Protocols, Female, Humans, Lymphocyte Activation, Membrane Glycoproteins, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasms, Receptors, Immunologic, Tumor Cells, Cultured, Signal Transduction, Lymphocytes, Tumor-Infiltrating, CD8-Positive T-Lymphocytes, Coculture Techniques, Drug Resistance, Neoplasm, Cell Line, Tumor, Mice, HEK293 Cells, Tumor Microenvironment, Programmed Cell Death 1 Receptor
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