Puisieux, I. | Search bioRxiv

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↗

bioRxiv2022

Spatial positioning and matrix programs of cancer-associated fibroblasts promote T cell exclusion in human lung tumors

It is currently accepted that activated cancer-associated fibroblasts (CAF) participate in T cell exclusion from tumor nests, but it remains unclear how they promote barrier phenotypes, and whether specific subsets are involved. Here, using single-cell RNA sequencing coupled with multiplex imaging on a large cohort of lung tumors, we identify four main CAF populations, of which only two are associated with T cell exclusion: (i) MYH11+SMA+ CAF, which are present in early-stage tumors and form a single-cell layer lining cancer aggregates, and (ii) FAP+SMA+ CAF, which appear in more advanced tumors and organize in patches within the stroma or in multiple layers around tumor nests. Both CAF populations show a contractility phenotype together with dense and aligned matrix fiber deposition compared to the T cell-permissive CAF. Yet they express distinct matrix genes, including COL4A1/COL9A1 (MYH11+SMA+ CAF) and COL11A1/COL12A1 (FAP+SMA+ CAF). Hereby, we uncovered unique molecular programs of CAF driving T cell marginalization, whose targeting should increase immunotherapy efficacy in patients bearing T cell-excluded tumors. SIGNIFICANCEThe cellular and molecular programs driving T cell marginalization in solid tumors remain unclear. Here, we describe two CAF populations associated with T cell exclusion in human lung tumors. We demonstrate the importance of pairing molecular and spatial analysis of the tumor microenvironment, a prerequisite to develop new strategies targeting T cell-excluding CAF.

cancer biology↗