Using pancreatic tumor models with high and low TILs, Sanctis and Dusi et al. demonstrated the role of CLDN18 in regulating host tumor immunity. CLDN18 expression supported T cell infiltration and immune-mediated tumor control. In human PDAC, CLDN18 expression correlated with differentiated histology and a favorable prognosis. Mechanistically, CLDN18 formed supramolecular complexes with adhesion molecules and intracellular cytoskeletal proteins, stabilizing ALCAM in lipid rafts and strengthening T cell–tumor cell contacts, leading to the formation of the immunological synapse, T cell activation, cytotoxicity, and cytokine release.
Contributed by Shishir Pant
ABSTRACT: 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.
Author Info: (1) Section of Immunology, Department of Medicine, University of Verona, Verona, Italy. Electronic address: francesco.desanctis@univr.it. (2) Veneto Institute of Oncology IOV-IRCCS
Author Info: (1) Section of Immunology, Department of Medicine, University of Verona, Verona, Italy. Electronic address: francesco.desanctis@univr.it. (2) Veneto Institute of Oncology IOV-IRCCS, Padua, Italy. (3) Veneto Institute of Oncology IOV-IRCCS, Padua, Italy. (4) Section of Immunology, Department of Medicine, University of Verona, Verona, Italy. (5) Section of Immunology, Department of Medicine, University of Verona, Verona, Italy. (6) Section of General Pathology, Department of Medicine, University of Verona, Verona, Italy. (7) Section of General Pathology, Department of Medicine, University of Verona, Verona, Italy. (8) Biopharmaceutical New Technologies (BioNTech) Corporation, Mainz, Germany. (9) Biopharmaceutical New Technologies (BioNTech) Corporation, Mainz, Germany. (10) Biopharmaceutical New Technologies (BioNTech) Corporation, Mainz, Germany; Institute of Pathology, School of Medicine, TUM, Munich, Germany. (11) Comparative Experimental Pathology (CEP), Institute of Pathology, School of Medicine, Technical University of Munich, Munich, Germany. (12) Comparative Experimental Pathology (CEP), Institute of Pathology, School of Medicine, Technical University of Munich, Munich, Germany. (13) Department of Medicine, University of California, San Diego, San Diego, CA, USA. (14) Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, Scotland. (15) Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland. (16) Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland. (17) Department of Engineering for Innovation Medicine, University of Verona, Verona, Italy. (18) Department of Computer Science, University of Verona, Verona, Italy. (19) Veneto Institute of Oncology IOV-IRCCS, Padua, Italy. (20) Department of Engineering for Innovation Medicine, University of Verona, Verona, Italy; ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy. (21) Department of Engineering for Innovation Medicine, University of Verona, Verona, Italy; ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy. (22) ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy; Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy. (23) Section of General Pathology, Department of Medicine, University of Verona, Verona, Italy; The Center for Biomedical Computing (CBMC), University of Verona, Verona, Italy. (24) Section of Immunology, Department of Medicine, University of Verona, Verona, Italy. (25) TRON-Translational Oncology at the University Medical Centre of the Johannes Gutenberg University, Mainz, Germany. (26) Biopharmaceutical New Technologies (BioNTech) Corporation, Mainz, Germany; University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. (27) Biopharmaceutical New Technologies (BioNTech) Corporation, Mainz, Germany; University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. (28) Veneto Institute of Oncology IOV-IRCCS, Padua, Italy. Electronic address: vincenzo.bronte@iov.veneto.it.
