Abstract 1129: Targeting tissue-resident macrophage progenitors restores anti-tumor immunity and suppresses tumor growth

Macrophages are innate immune cells that accumulate rapidly in tumors, where they promote immune suppression, tumor growth and resistance to checkpoint inhibitor therapy. As these cells play critical roles in tumor progression, they are the focus of efforts to develop novel cancer therapeutics. Strategies to inhibit macrophage accumulation to suppress tumor growth by blocking their recruitment from circulation have been only partially effective. In this project, we examined the origins of tumor associated macrophages using lineage tracing, flow cytometry, and single cell sequencing. We found that large proportions of macrophages in subcutaneous and genetically engineered mouse tumors do not derive from Ly6C+ or Ly6C- or CCR2+ monocytes. Instead, a large population of CCR2-Ly6C-F4/80hi macrophages that are CD206+MerTK+ are profoundly immune suppressive resident macrophages that arise from a transcriptionally related proliferative progenitor subpopulation rather than by trafficking from the circulation. By comparing gene expression profiles of resident and recruited macrophages in subcutaneous, alveolar, central nervous and renal normal and tumor tissues, we identified generic tissue resident macrophage and recruited signatures that reveal that resident macrophages are more immune suppressive than recruited macrophages and are associated with worse outcomes in cancer patients. Tissue resident macrophages express signatures of Myc-driven proliferation, cholesterol metabolism and profound immune suppression while bone marrow derived macrophages express mixed signatures of inflammation and immune suppression. Genetic and pharmacological inhibition of c-Kit/mCsf1R, cMyc and cyclin-dependent kinases suppressed the expansion of these macrophages, thereby limiting their accumulation in tumors, promoting anti-tumor adaptive immunity and inhibiting tumor progression in mouse models of cancer. We identified a novel cKit/Csf1r/Cdk19 inhibitor that suppressed tissue resident macrophage accumulation and potently inhibited tumor growth. These results identify tissue resident macrophage progenitor cells as key targets for the development of therapeutic strategies to stimulate anti-cancer immunity. Citation Format: Hui Chen, Marc Paradise, Ryan Shepard, Guangfang Wang, Mark Onaitis, Judith Varner. Targeting tissue-resident macrophage progenitors restores anti-tumor immunity and suppresses tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1129.