biostudies-literatureWang ZCedar Hill FoundationLustgarten FoundationNCI NIH HHSThompson Family FoundationNIGMS NIH HHSe2119463119https://www.ebi.ac.uk/biostudies/studies/S-EPMC8794816biostudies-literatureUnknown119(4)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 Proceedings of the National Academy of Sciences of the United States of AmericaCarcinomas assemble a filamentous CXCL12-keratin-19 coating that suppresses T cell-mediated immune attack.PMC8794816Distinguished Scholar AwardF30 CA265134No reference numberP30 CA008748T32 GM008444P30 CA045508Moresco PFearon DTLi JBiasci DYao MJanowitz TYan RHechtman JFPearson JZaidi RMWeiss MJGao YWang ZfalseCarcinomas assemble a filamentous CXCL12-keratin-19 coating that suppresses T cell-mediated immune attack.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 2022-01-01T00:00:00Z2022 Jan2025-04-22T15:23:08.212Z2025-04-06T01:19:47.568ZS-EPMC87948163504604910.1073/pnas.2119463119