Abstract 189P
Background
There is an urgent need to improve the safety and efficacy of immunotherapy, which has focused primarily on the adaptive immune system. Macrophages are the most common infiltrating immune cells in tumors and they can be directed to kill cancer cells by targeting macrophage-specific immune checkpoints, such as the CD47/SIRPa axis. CD47 serves as a “don’t eat me” signal on cancer cells and binds to SIRPa on macrophages to inhibit phagocytosis. Cytokines can influence macrophage polarization states, but how cytokines influence macrophage activation, particularly in the setting of macrophage checkpoint blockade, remains unknown.
Methods
To study how cytokines modulate macrophage anti-tumor function, we conducted an unbiased screen of 113 recombinant human cytokines using a novel co-culture assay that measures long-term interactions between primary human macrophages and human cancer cells. We tested how each cytokine alters macrophage-mediated cytotoxicity at baseline or in the presence of CD47 blockade. In validation studies, we tested more generally if candidate cytokines could enhance the macrophage response to tumor-opsonizing antibodies such as cetuximab (anti-EGFR mAb). We also confirmed the cross-species relevance of these findings in a murine in vitro system.
Results
Surprisingly, we found that despite not having single-agent activity, interleukin 10 (IL-10) synergizes with anti-CD47 therapy to enhance human macrophage anti-tumor function in long-term co-culture with non-small cell lung cancer (NSCLC) cells. These findings were conserved in a murine model of NSCLC in vitro. IL-10 also synergizes with tumor opsonizing antibodies, such as cetuximab, to enhance macrophage killing of cancer cells. IL-10 priming of macrophages enhanced antibody-dependent phagocytosis of multiple cancer cell lines, likely underlying its mechanism of action.
Conclusions
We discovered an unexpected role for IL-10 in enhancing macrophage anti-tumor functions in response to CD47 blockade and tumor-opsonizing antibodies. These findings illuminate a novel strategy to harness macrophages for cancer immunotherapy and provides preclinical rationale for testing this therapeutic combination in patients with cancer.
Legal entity responsible for the study
The authors.
Funding
Whitehead Institute.
Disclosure
A. Maoz: Non-Financial Interests, Personal, Other, Patent application: Whitehead Institute. K. Vaccaro: Financial Interests, Personal, Full or part-time Employment: DEM Biopharma; Financial Interests, Personal, Stocks/Shares: Orchard therapeutics. K. Weiskopf: Financial Interests, Personal, Advisory Board, Scientific co-founder, SAB member, equity ownership, royalties: ALX Oncology; Financial Interests, Personal, Advisory Board, Scientific co-founder, SAB member, equity ownership, royalties, compensation: DEM Biopharma; Financial Interests, Personal, Other, Scientific advisor, compensation: Carisma Therapeutics; Financial Interests, Personal, Stocks/Shares: Adaptimmune, Gingko Bioworks, Guardant Health, Immunity Bio, Myovant Sciences, Arbutus Biopharma, Arvinas Inc, Beyond Air, Biomarin Pharmaceutical Inc, Trillium Therapeutics, Bluebird Bio, Medicenna Therapeutics, Kura Oncology, Sesen Bio; Financial Interests, Personal, Royalties, Patents, royalties, and licensing fees: Stanford University; Financial Interests, Personal, Other, Patent applications, anticipated royalties and licensing fees: Whitehead Institute; Financial Interests, Personal, Invited Speaker, Royalties and licensing fees: Gilead Sciences, Inc; Financial Interests, Personal and Institutional, Research Grant: AACR-AstraZeneca Career Development Award for Physician-Scientists, in Honor of José Baselga. All other authors have declared no conflicts of interest.