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Tumor Associated Macrophages (TAMs) promote tumor survival, angiogenesis and metastases. Although they express MHC Class II molecules, little is known about their ability to present tumor antigens to tumor infiltrating CD4 T cells, nor what are the consequences of such presentation. To answer these questions, we used a C57/BL10 mouse tumor model where we subcutaneously implant a bladder carcinoma cell line naturally expressing the H-Y male antigen into female mice, making the H-Y antigen a de facto neoantigen. We found that TAMs indeed present tumor antigens to effector CD4 T cells and that such presentation is necessary for tumor rejection. As consequence of this interaction TAMs are re-educated to produce lower amounts of tumor promoting proteins and greater amounts of inflammatory proteins. The re-education process of the TAMs is transcriptionally characterized by an IFN-g signature, including genes of known anti-viral and anti-bacterial functions. CD4 production of IFN-g, and not TNF-a or CD40L, is required for the re-education process and tumor rejection. Furthermore, IFN-g signaling on antigen presenting TAMs and not on bystander TAMs, is necessary for the anti-tumor effect. These data identify critical mechanisms of tumor rejection by CD4 T cells and underscores the importance of effector CD4 T cell-tissue macrophage interactions not only at the tumors site but potentially in other tissues.

Neoantigen Presentation and IFNγ Signaling on the Same Tumor-associated Macrophage are Necessary for CD4 T Cell–mediated Antitumor Activity in Mice