Carcinomas assemble a filamentous CXCL12-keratin-19 coating that suppresses T cell-mediated immune attack.
Hechtman, Jaclyn F
Zaidi, Raza M
Weiss, Matthew J
Proc Natl Acad Sci U S A
Proceedings of the National Academy of Sciences
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Wang, Z., Moresco, P., Yan, R., Li, J., Gao, Y., Biasci, D., Yao, M., et al. (2022). Carcinomas assemble a filamentous CXCL12-keratin-19 coating that suppresses T cell-mediated immune attack.. Proc Natl Acad Sci U S A, 119 (4) https://doi.org/10.1073/pnas.2119463119
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.
T cells, Cxcl12, Cancer Immunology, Keratin-19, Transglutaminase-2
NIGMS NIH HHS (T32 GM008444)
External DOI: https://doi.org/10.1073/pnas.2119463119
This record's URL: https://www.repository.cam.ac.uk/handle/1810/334262
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/