Expression of the membrane tetraspanin claudin 18 on cancer cells promotes T lymphocyte infiltration and antitumor immunity in pancreatic cancer.

Tumors weakly infiltrated by T lymphocytes poorly respond to immunotherapy. We aimed to unveil malignancy-associated programs regulating T cell entrance, arrest, and activation in the tumor environment. Differential expression of cell adhesion and tissue architecture programs, particularly the presence of the membrane tetraspanin claudin (CLDN)18 as a signature gene, demarcated immune-infiltrated from immune-depleted mouse pancreatic tumors. In human pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer, CLDN18 expression positively correlated with more differentiated histology and favorable prognosis. CLDN18 on the cell surface promoted accrual of cytotoxic T lymphocytes (CTLs), facilitating direct CTL contacts with tumor cells by driving the mobilization of the adhesion protein ALCAM to the lipid rafts of the tumor cell membrane through actin. This process favored the formation of robust immunological synapses (ISs) between CTLs and CLDN18-positive cancer cells, resulting in increased T cell activation. Our data reveal an immune role for CLDN18 in orchestrating T cell infiltration and shaping the tumor immune contexture. Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Francesco De Sanctis, Silvia Dusi, Simone Caligola, Cristina Anselmi, Varvara Petrova, Barbara Rossi, Gabriele Angelini, Michael Erdeljan, Stefan Wöll, Anna Melissa Schlitter, Thomas Metzler, Katja Steiger, Zea Borok, Peter Bailey, Aline Bauer, Cornelia Halin, Federico Boschi, Rosalba Giugno, Stefania Canè, Rita Lawlor, Vincenzo Corbo, Aldo Scarpa, Gabriela Constantin, Stefano Ugel, Fulvia Vascotto, Ugur Sahin, Özlem Türeci, Vincenzo Bronte. Expression of the membrane tetraspanin claudin 18 on cancer cells promotes T lymphocyte infiltration and antitumor immunity in pancreatic cancer. Immunity. 2024 Jun 11;57(6):1378-1393.e14

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PMID: 38749447

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