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

Tumor-associated macrophages (TAM) 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, and 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 a consequence of this interaction, TAMs are reeducated to produce lower amounts of tumor-promoting proteins and greater amounts of inflammatory proteins. The reeducation process of the TAMs is transcriptionally characterized by an IFNγ signature, including genes of known antiviral and antibacterial functions. CD4 production of IFNγ, and not TNFα or CD40L, is required for the reeducation process and tumor rejection. Furthermore, IFNγ signaling on antigen-presenting TAMs and not on bystander TAMs, is necessary for the antitumor 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. SIGNIFICANCE: In the tumor microenvironment, TAMs are capable of presenting tumor antigens to effector CD4 T cells. Upon antigen recognition, the CD4 cells transform transcriptionally, phenotypically, and functionally the TAMs inducing tumor rejection. This reeducation process requires both cognate interaction and IFNγ signaling on the same macrophage.