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

Nom de la revue
Preprint bioRxiv
John A. Grout, Philémon Sirven, Andrew M. Leader, Shrisha Maskey, Eglantine Hector, Isabelle Puisieux, Fiona Steffan, Evan Cheng, Navpreet Tung, Mathieu Maurin, Romain Vaineau, Léa Karpf, Martin Plaud, Maria Casanova-Acebes, Alexandra Tabachnikova, Shilpa Keerthivasan, Alona Lansky, Jessica LeBérichel, Laura Walker, Adeeb H. Rahman, Sacha Gnjatic, Julien Adam, Jerome C. Martin, Andrea Wolf, Raja Flores, Mary Beth Beasley, Rachana Pradhan, Sören Müller, Thomas U. Marron, Shannon J. Turley, Miriam Merad, Ephraim Kenigsberg, Hélène Salmon

SUMMARYIt 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+αSMA+ CAF, which are present in early-stage tumors and form a single-cell layer lining cancer aggregates, and (ii) FAP+αSMA+ 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+αSMA+ CAF) and COL11A1/COL12A1 (FAP+αSMA+ 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.