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


Type
Article
Change log
Authors
Moresco, Philip 
Yan, Ran 
Li, Jiayun 
Gao, Ya 
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.

Description
Keywords
CXCL12, T cells, cancer immunology, keratin-19, transglutaminase-2, Animals, Breast Neoplasms, Carcinoma, Cell Line, Tumor, Chemokine CXCL12, Cytotoxicity, Immunologic, Female, Humans, Keratin-19, Male, Mice, Microsatellite Repeats, Pancreatic Neoplasms, Protein Binding, Protein Multimerization, T-Lymphocytes
Journal Title
Proc Natl Acad Sci U S A
Conference Name
Journal ISSN
0027-8424
1091-6490
Volume Title
119
Publisher
Proceedings of the National Academy of Sciences
Sponsorship
NIGMS NIH HHS (T32 GM008444)