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, angiogen-esis, 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 subcuta-neously implant a bladder carcinoma cell line naturally expressing the H-Y male antigen into female mice, making the H-Y antigen a de facto neoanti-gen. 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 inflamma-tory proteins. The reeducation process of the TAMs is transcriptionally characterized by an IFN & gamma; signature, including genes of known antiviral and antibacterial functions. CD4 production of IFN & gamma;, and not TNF & alpha; or CD40L, is required for the reeducation process and tumor rejection. Furthermore, IFN & gamma; 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 effec-tor 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 pre-senting 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 IFN & gamma; signaling on the same macrophage.