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

Abstract

Tumor-associated macrophages (TAM) promote tumor survival, angiogen- antibacterial functions. CD4 production of IFNγ, and not TNFα or CD40L, esis, and metastases. Although they express MHC class II molecules, little is required for the reeducation process and tumor rejection. Furthermore, is known about their ability to present tumor antigens to tumor-infiltrating IFNγ signaling on antigen-presenting TAMs and not on bystander TAMs, is CD4 T cells, and the consequences of such presentation. To answer these necessary for the antitumor effect. These data identify critical mechanisms questions, we used a C57/BL10 mouse tumor model where we subcuta- of tumor rejection by CD4 T cells and underscores the importance of effecneously implant a bladder carcinoma cell line naturally expressing the H-Y tor CD4 T cell–tissue macrophage interactions not only at the tumors site male antigen into female mice, making the H-Y antigen a de facto neoanti- but potentially in other tissues. gen. We found that TAMs indeed present tumor antigens to effector CD4 Significance: In the tumor microenvironment, TAMs are capable of preT cells and that such presentation is necessary for tumor rejection. As a senting tumor antigens to effector CD4 T cells. Upon antigen recognition, consequence of this interaction, TAMs are reeducated to produce lower the CD4 cells transform transcriptionally, phenotypically, and functionally amounts of tumor-promoting proteins and greater amounts of inflamma- the TAMs inducing tumor rejection. This reeducation process requires both tory proteins. The reeducation process of the TAMs is transcriptionally cognate interaction and IFNγ signaling on the same macrophage. characterized by an IFNγ signature, including genes of known antiviral and