Type 1 conventional dendritic cells and interferons are required for spontaneous CD4+ and CD8+ T‐cell protective responses to breast cancer

Abstract

Abstract Objectives To better understand how immune responses may be harnessed against breast cancer, we investigated which immune cell types and signalling pathways are required for spontaneous control of a mouse model of mammary adenocarcinoma. Methods The NOP23 mammary adenocarcinoma cell line expressing epitopes derived from the ovalbumin model antigen is spontaneously controlled when orthotopically engrafted in syngeneic C57BL/6 mice. We combined this breast cancer model with antibody‐mediated depletion of lymphocytes and with mutant mice affected in interferon (IFN) or type 1 conventional dendritic cell (cDC1) responses. We monitored tumor growth and immune infiltration including the activation of cognate ovalbumin‐specific T cells. Results Breast cancer immunosurveillance required cDC1, NK/NK T cells, conventional CD4+ T cells and CD8+ cytotoxic T lymphocytes (CTLs). cDC1 were required constitutively, but especially during T‐cell priming. In tumors, cDC1 were interacting simultaneously with CD4+ T cells and tumor‐specific CTLs. cDC1 expression of the XCR1 chemokine receptor and of the T‐cell‐attracting or T‐cell‐activating cytokines CXCL9, IL‐12 and IL‐15 was dispensable for tumor rejection, whereas IFN responses were necessary, including cDC1‐intrinsic signalling by STAT1 and IFN‐γ but not type I IFN (IFN‐I). cDC1 and IFNs promoted CD4+ and CD8+ T‐cell infiltration, terminal differentiation and effector functions. In breast cancer patients, high intratumor expression of genes specific to cDC1, CTLs, CD4+ T cells or IFN responses is associated with a better prognosis. Conclusion Interferons and cDC1 are critical for breast cancer immunosurveillance. IFN‐γ plays a prominent role over IFN‐I in licensing cDC1 for efficient T‐cell activation.

Keywords

• breast cancer
• cancer immunosurveillance
• CD4+ T cells
• CD8+ T cells
• cDC1
• IFN‐γ