cDC1 and interferons promote spontaneous CD4⁺ and CD8⁺ T cell protective responses to breast cancer

Abstract

Here we show that efficient breast cancer immunosurveillance relies on cDC1, conventional CD4+ T cells, CD8+ cytotoxic T lymphocytes (CTL) and later NK/NK T cells. For this process, cDC1 were required constitutively, but especially during the T cell priming phase. In the tumor microenvironment, cDC1 interacted physically and jointly with both CD4+ T cells and tumorspecific CD8+ T cells. We found that interferon (IFN) responses were necessary for the rejection of breast cancer, including cDC1-intrinsic signaling by IFN-γ and STAT1. Surprisingly, cell-intrinsic IFN-I signaling in cDC1 was not required. cDC1 and IFNs shaped the tumor immune landscape, notably by promoting CD4+ and CD8+ T cell infiltration, terminal differentiation and effector functions. XCR1, CXCL9, IL-12 and IL-15 were individually dispensable for breast cancer immunosurveillance. Consistent with our experimental results in mice, high expression in the tumor microenvironment of genes specific to cDC1, CTL, helper T cells or interferon responses are associated with a better prognosis in human breast cancer patients. Our results show that immune control of breast cancer depends on cDC1 and IFNs as previously reported for immunogenic melanoma or fibrosarcoma tumor models, but that the underlying mechanism differ. Revisiting cDC1 functions in the context of spontaneous immunity to cancer should help defining new ways to mobilize cDC1 functions to improve already existing immunotherapies for the benefits of patients.SynopsisType 1 conventional dendritic cells cross-present tumor antigens to CD8+ T cells. Understanding the regulation of their antitumor functions is important. Cell-intrinsic STAT1/IFN-γ signaling licenses them for efficient CD4+ and CD8+ T cell activation during breast cancer immunosurveillance.

Immune landscape and risk prediction based on pyroptosis-related molecular subtypes in triple-negative breast cancer

“…In line with previous studies, we discovered a positive correlation between the increase in the risk score and the p r o p o r t i o n o f M 2 m a c r o p h a g e s i n t h e i m m u n e microenvironment of TNBC, while the presence of M1 macrophages was negatively associated with the value of the risk score in patients. Dendritic cells, which are critical for T-cell activation and immunosurveillance in BC (57), also showed a lower infiltration rate as the risk score increased according to our findings. The correlation between immune cell abundance and pyroptosis-related risk stratification in our study implied the pivotal role of pyroptosis in shaping an activated antitumor microenvironment in TNBC.…”