Aire-expressing tumor-associated macrophages promote cancer immune evasion 3704

Abstract Description Many cancers evade detection by co-opting intrinsic mechanisms of immune tolerance, limiting immunotherapy responses. Peripheral immune cells expressing the Autoimmune Regulator (Aire) gene play critical roles in immune tolerance, but their roles in cancer remain unexplored. Here we identified tumor-associated macrophages expressing Aire (Aire+ TAMs) that suppress anti-tumor CD8+ T cell responses. Analogous Aire+ TAMs also exist in human cancers and associate with unfavorable clinical outcomes. Depletion of Aire+ TAMs restrained tumor growth, and conditional Aire deletion in the macrophage lineage enabled synergistic responses to immune checkpoint inhibitors in otherwise resistant models. Aire regulates the abundance and transcriptional state of this tolerogenic TAM population in a cell-intrinsic fashion. These previously undescribed Aire-mediated mechanisms of peripheral tolerance represent promising targets in malignancies resistant to current immunotherapies. Funding Sources Supported by NIH grants CA271748; T32GM1365471; T32GM00856825; CA288017; T32AI007334; T32GM136547; R01DR032033; OD023056; OD018040; AI172348; 5T32AI0073343; AACR award 20-20-01-SPIT; Burroughs Welcome Fund; Pew Biomedical Scholars Grant; DOD US Army Med. Res. Acq. Activity Award BC220499; CRI award CRI4437; UCSF Sandler Fellows Physician Scientist Scholars Program Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)