Sanlaville, A. | bioRxiv Science

bioRxiv2023

CD4 T cells and neutrophils contribute to epithelial-mesenchymal transition in breast cancer

Epithelial-mesenchymal transition (EMT) is a central oncogenic mechanism, contributing both to transformation and metastatic dissemination. Inflammation and innate immune cells are known to favor EMT induction, but the role of adaptive immunity still remains unclear. Using an original murine mammary tumor model in immune cell subpopulation depletion experiments, we demonstrated that tumor cells maintain their epithelial phenotype in mice deficient for adaptive immune response, but undergo EMT in the presence of T-cells. This phenotypic conversion involves the major contribution of CD4 T cells, but not CD8 T cells nor B cells, undoubtedly demonstrating the pro-EMT role of CD4 T cells specifically among adaptive immune cells. Moreover, combined intra-tumor immune infiltrate and transcriptomic analyses of murine mammary tumors with various EMT phenotype revealed an inverse correlation between mesenchymal tumor cell and intratumoral neutrophil proportions, due to the reduced ability of mesenchymal cells to recruit neutrophils. Last, selective in vivo depletion of neutrophils and transcriptomic analysis of human breast tumor cohorts demonstrated the pro-EMT role of neutrophils and suggest a cooperation with CD4 T cells in EMT promotion. Collectively, our data highlight a novel mechanism of EMT regulation by both innate and adaptive immune compartments.

cancer biology↗

bioRxiv2020

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

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-{gamma} 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-{gamma} signaling licenses them for efficient CD4+ and CD8+ T cell activation during breast cancer immunosurveillance.

immunology↗