Carcinomas assemble a filamentous CXCL12-keratin-19 coating that suppresses T cell-mediated immune attack

Wang, Zhikai, Moresco, Philip, Yan, Ran, Li, Jiayun, Gao, Ya, Biasci, Daniele, Yao, Min, Pearson, Jordan, Hechtman, Jaclyn F, Janowitz, Tobias, Zaidi, Raza M, Weiss, Matthew J, Fearon, Douglas T (January 2022) Carcinomas assemble a filamentous CXCL12-keratin-19 coating that suppresses T cell-mediated immune attack. Proceedings of the National Academy of Sciences of USA, 119 (4). e2119463119-e2119463119. ISSN 0027-8424

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Abstract

Cancer immunotherapy frequently fails because most carcinomas have few T cells, suggesting that cancers can suppress T cell infiltration. Here, we show that cancer cells of human pancreatic ductal adenocarcinoma (PDA), colorectal cancer, and breast cancer are coated with transglutaminase-2 (TGM2)-dependent covalent CXCL12-keratin-19 (KRT19) heterodimers that are organized as filamentous networks. Since a dimeric form of CXCL12 suppresses the motility of human T cells, we determined whether this polymeric CXCL12-KRT19 coating mediated T cell exclusion. Mouse tumors containing control PDA cells exhibited the CXCL12-KRT19 coating, excluded T cells, and did not respond to treatment with anti-PD-1 antibody. Tumors containing PDA cells not expressing either KRT19 or TGM2 lacked the CXCL12-KRT19 coating, were infiltrated with activated CD8+ T cells, and growth was suppressed with anti-PD-1 antibody treatment. Thus, carcinomas assemble a CXCL12-KRT19 coating to evade cancer immune attack.

Item Type:	Paper
Subjects:	organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells diseases & disorders > cancer > cancer types > breast cancer diseases & disorders > cancer > cancer types > colorectal diseases & disorders > cancer > drugs and therapies > Immunotherapy diseases & disorders > cancer > cancer types > pancreatic cancer
CSHL Authors:	Wang, Zhikai Moresco, Philip Yan, Ran Li, Jiayun Yao, Min Janowitz, Tobias Fearon, Douglas Gao, Ya Pearson, Jordan
Communities:	CSHL labs > Fearon lab CSHL labs > Janowitz lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	25 January 2022
Date Deposited:	26 Jan 2022 16:34
Last Modified:	10 Feb 2022 20:31
PMCID:	PMC8794816
URI:	https://repository.cshl.edu/id/eprint/40501

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