意大利威尼托肿瘤研究所Vincenzo Bronte等研究人员合作发现，癌细胞中四跨膜蛋白claudin 18的表达可促进胰腺癌中T淋巴细胞的浸润和抗肿瘤免疫。该项研究成果发表在2024年5月14日出版的《免疫》上。

研究人员的目标是揭示与恶性肿瘤相关的程序，这些程序调节T细胞在肿瘤环境中的进入、停滞和活化。细胞粘附和组织结构程序的差异表达，特别是作为特征基因的四跨膜蛋白claudin（CLDN）18的存在，将免疫浸润的小鼠胰腺肿瘤与免疫耗竭的小鼠胰腺肿瘤区分开来。在人类胰腺导管腺癌（PDAC）和非小细胞肺癌中，CLDN18的表达与组织学分化程度和良好预后呈正相关。

细胞表面的CLDN18可促进细胞毒性T淋巴细胞（CTL）的增殖，通过肌动蛋白将粘附蛋白ALCAM调集到肿瘤细胞膜的脂质筏，从而促进CTL与肿瘤细胞的直接接触。这一过程有利于CTL与CLDN18阳性癌细胞之间形成强大的免疫突触 (IS)，从而增加T细胞的活化。这些数据揭示了CLDN18在协调T细胞浸润和塑造肿瘤免疫环境中的免疫作用。

据了解，T淋巴细胞浸润较弱的肿瘤对免疫疗法的反应较差。

附：英文原文

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

Author: Francesco De Sanctis, Silvia Dusi, Simone Caligola, Cristina Anselmi, Varvara Petrova, Barbara Rossi, Gabriele Angelini, Michael Erdeljan, Stefan Wll, 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, zlem Türeci, Vincenzo Bronte

Issue&Volume: 2024-05-14

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.

DOI: 10.1016/j.immuni.2024.04.021

Source: https://www.cell.com/immunity/fulltext/S1074-7613(24)00226-7