Carcinomas assemble a filamentous CXCL12–keratin-19 coating that suppresses T cell–mediated immune attack
Menée à l'aide d'échantillons tumoraux et de modèles murins, cette étude met en évidence la présence sur des cellules cancéreuses d'un revêtement filamenteux, composé de molécules de kératine 19 et de chimiokines CXCL12, qui supprime la réponse immunitaire induite par les lymphocytes T
Carcinomas resist immunotherapy because T cells are absent from nests of cancer cells. The chemokine/chemokine receptor system, which regulates the migration of immune cells, is a candidate for this impaired intratumoral accumulation of T cells. Cancer cells in human pancreatic, colorectal, and breast cancers are coated with the chemokine CXCL12 in the form of covalent heterodimers with keratin-19. This CXCL12 coating was investigated using a mouse model of pancreatic cancer that replicates the immunological characteristics of human cancer. Mouse pancreatic cancer cells without the CXCL12 coating formed tumors that did not exclude T cells and responded to anti–PD-1 antibody treatment. Thus, the ability of cancer cells to coat themselves with CXCL12 may contribute to resistance to immunotherapy.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.