Carcinomas assemble a filamentous CXCL12-keratin-19 coating that suppresses T cell-mediated immune attack.
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Authors
Moresco, Philip
Yan, Ran
Li, Jiayun
Gao, Ya
Biasci, Daniele
Yao, Min
Pearson, Jordan
Hechtman, Jaclyn F
Zaidi, Raza M
Weiss, Matthew J
Publication Date
2022-01-25Journal Title
Proc Natl Acad Sci U S A
ISSN
0027-8424
Publisher
Proceedings of the National Academy of Sciences
Volume
119
Issue
4
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
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
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.
Keywords
T cells, Cxcl12, Cancer Immunology, Keratin-19, Transglutaminase-2
Sponsorship
NIGMS NIH HHS (T32 GM008444)
Identifiers
PMC8794816, 35046049
External DOI: https://doi.org/10.1073/pnas.2119463119
This record's URL: https://www.repository.cam.ac.uk/handle/1810/334262
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