Perez-Diez et al. showed that female mice totally lacking CD8+ T cells rejected s.c. implanted syngeneic H-Y male antigen+ murine bladder carcinoma cells. CD4+ T cells were essential for rejection, and recognized H-Y as a tumor neoantigen presented by BM-derived myeloid cells. TAMs in the TME were identified as the MHC-II+ cells that captured H-Y. Tumor-specific CD4+ T cells produced IFNγ, which induced TAMs to express an inflammatory rather than tumor-promoting macrophage phenotype. Maximal rejection required both cognate CD4+ T cell interaction with and IFNγ signaling of the same, and not bystander, TAMs.
Contributed by Paula Hochman
ABSTRACT: 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-γ signature, including genes of known anti-viral and anti-bacterial functions. CD4 production of IFN-γ, and not TNF-α or CD40L, is required for the re-education process and tumor rejection. Furthermore, IFN-γ 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.
Author Info: (1) Ghost Lab, T Cell Memory and Tolerance Section, Laboratory of Cellular and Molecular Immunology, National Institutes of Allergy and Infectious Diseases, National Institutes of
Author Info: (1) Ghost Lab, T Cell Memory and Tolerance Section, Laboratory of Cellular and Molecular Immunology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. (2) Ghost Lab, T Cell Memory and Tolerance Section, Laboratory of Cellular and Molecular Immunology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. (3) Ghost Lab, T Cell Memory and Tolerance Section, Laboratory of Cellular and Molecular Immunology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
