Spatial Positioning and Matrix Programs of Cancer-Associated Fibroblasts Promote T-cell Exclusion in Human Lung Tumors

• Published in: Cancer discovery Vol. 12; no. 11; pp. 2606 - 2625
• Main Authors: Grout, John A, Sirven, Philemon, Leader, Andrew M, Maskey, Shrisha, Hector, Eglantine, Puisieux, Isabelle, Steffan, Fiona, Cheng, Evan, Tung, Navpreet, Maurin, Mathieu, Vaineau, Romain, Karpf, Lea, Plaud, Martin, Begue, Anne-Laure, Ganesh, Koushik, Mesple, Jérémy, Casanova-Acebes, Maria, Tabachnikova, Alexandra, Keerthivasan, Shilpa, Lansky, Alona, Berichel, Jessica Le, Walker, Laura, Rahman, Adeeb H, Gnjatic, Sacha, Girard, Nicolas, Lefevre, Marine, Damotte, Diane, Adam, Julien, Martin, Jerome C, Wolf, Andrea, Flores, Raja M, Beasley, Mary Beth, Pradhan, Rachana, Muller, Soren, Marron, Thomas U, Turley, Shannon J, Merad, Miriam, Kenigsberg, Ephraim, Salmon, Hélène
• Format: Journal Article
• Language: English
• Published: United States 02.11.2022
• Subjects: Cancer-Associated Fibroblasts - pathology; Fibroblasts; Humans; Immunotherapy - methods; Life Sciences; Lung Neoplasms - pathology; T-Lymphocytes; Tumor Microenvironment
• ISSN: 2159-8274; 2159-8290; 2159-8290
• DOI: 10.1158/2159-8290.CD-21-1714

It is currently accepted that cancer-associated fibroblasts (CAF) participate in T-cell exclusion from tumor nests. To unbiasedly test this, we used single-cell RNA sequencing coupled with multiplex imaging on a large cohort of lung tumors. We identified four main CAF populations, two of which 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 populations orchestrate a particular structural tissue organization through dense and aligned fiber deposition compared with T cell-permissive CAF. Yet they produce distinct matrix molecules, including collagen IV (MYH11+αSMA+ CAF) and collagen XI/XII (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. The 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 developing new strategies targeting T cell-excluding CAF. See related commentary by Sherman, p. 2501. This article is highlighted in the In This Issue feature, p. 2483.