PO.IM02.03 · 免疫学

结直肠癌浸润细菌促进具有抗肿瘤特性的细胞毒性淋巴细胞群增殖

Colorectal cancer-infiltrating bacteria promote the proliferation of cytotoxic lymphocyte populations endowed with antitumor properties

编号 2865 展板 5 时间 4/20 02:00–05:00 区域 Section 9 主讲 Martina Villa

分会场 Microbiome, Inflammation, and Response to Immunotherapy in Cancer

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作者与单位 Authors & Affiliations

Martina Villa¹, Julija Djordjevic¹, Elisa Sorrenti², Pedro Ventura³, Davide Bressan⁴, Antonino Cassotta³, Caroline Junqueira³, Fulvio Chiacchiera⁴, Federica Sallusto³, Dimitrios Christoforidis⁵, Giandomenica Iezzi²

¹Institute for Translational Research USI-EOC, Ente Ospedaliero Cantonale, Bellinzona, Switzerland,²Ente Ospedaliero Cantonale, Bellinzona, Switzerland,³Institute for Research in Biomedicine, Bellinzona, Switzerland,⁴Department of Cellular, Computational, and Integrative Biology, University of Trento, Trento, Italy,⁵Department of Surgery, Ente Ospedaliero Cantonale, Lugano, Switzerland

摘要 Abstract

中文摘要

结直肠癌（CRC）是全球癌症死亡的第二大原因。在CRC癌变过程中，肠上皮屏障的改变使共生细菌能够从肠道转移到肿瘤组织，并与浸润性免疫细胞相互作用。细胞毒性T淋巴细胞的浸润与生存改善相关，但它们与肿瘤浸润细菌的潜在相互作用尚未得到充分研究。我们此前鉴定出一组细菌，其在CRC组织中的丰度与淋巴细胞浸润程度相关。在这项工作中，我们研究了这些细菌诱导淋巴细胞介导免疫应答的能力。将来自健康供体或患者的外周血单个核细胞与冷冻保存的目标细菌共培养，并基于CFSE稀释评估增殖。增殖细胞主要由表达γδTCR、尤其是Vδ2链的CD4-CD8-双阴性（DN）T细胞组成。在增殖细胞中还检测到CD4+和CD8+ TCRαβ+ T细胞。激活后，DN Vδ2+ T细胞释放IFNγ、TNFα、穿孔素和颗粒酶，提示具有细胞毒性潜力。它们同时表达NKG2D，促使我们研究其是否能介导针对CRC细胞系的肿瘤细胞杀伤。与CD4+和CD8+不同，细菌反应性DN T细胞表现出不依赖MHC的肿瘤细胞杀伤。通过大规模流式细胞术和原发性CRC样本的单细胞RNA测序进行的分析显示，肿瘤浸润淋巴细胞（TILs）中存在DN TCRγδ+ T细胞。有趣的是，它们的表型和转录组学特征被发现与来自外周血的细菌反应性DN T细胞部分重叠。DN TILs对CRC相关细菌的反应性目前正在研究中。细菌介导的CRC浸润DN T细胞激活可能有利于对肿瘤的双向靶向，促成有效的抗肿瘤免疫应答。

查看英文原文 English abstract

Colorectal cancer (CRC) is the second-leading cause of cancer deaths worldwide. During CRC carcinogenesis alteration of the gut epithelial barrier allows the translocation of commensal bacteria from the gut to the tumor tissue and their interaction with infiltrating immune cells. Infiltration by cytotoxic T lymphocytes is associated with improved survival, but their potential interplay with tumor-infiltrating bacteria has not been fully investigated.We previously identified a panel of bacteria whose abundance in CRC tissues correlates with the extent of lymphocytic infiltration. In this work, we have investigated the capacity of these bacteria to induce lymphocyte-mediated immune responses.Peripheral blood mononuclear cells from healthy donors or patients were cultured with cryopreserved bacteria of interest and assessed for proliferation based on CFSE dilution. Proliferating cells mostly consisted of CD4-CD8- double negative (DN) T cells expressing gammadeltaTCRs, and in particular the Vdelta2 chain. CD4+ and CD8+ TCRalphaß+ T cells were also detected among proliferating cells. Following activation, DN Vdelta2+ T cells released IFNg, TNFalpha, perforin, and granzymes suggesting a cytotoxic potential. Their concomitant expression of NKG2D led us to investigate whether they could mediate tumor-cell killing against CRC cell lines. In contrast to CD4+ and CD8+, bacteria-reactive DN T cells showed MHC-independent tumor cell killing.Analysis performed by large-scale flow cytometry and single-cell RNA sequencing of primary CRC samples revealed the presence of DN TCRgammadelta+ T cells among tumor-infiltrating lymphocytes (TILs). Interestingly, their phenotypes and transcriptomic profiles were found to partially overlap with those of bacteria-reactive DN T cells from peripheral blood. The reactivity of DN TILs to CRC-associated bacteria is currently under investigation.Bacteria-mediated activation of CRC-infiltrating DN T cells may favor a double-sided targeting of the tumor, contributing to an effective antitumor immune response.

利益披露 Disclosure

M. Villa, None.. J. Djordjevic, None.. P. Ventura, None.. D. Bressan, None.. A. Cassotta, None.. C. Junqueira, None.. F. Chiacchiera, None.. F. Sallusto, None.. D. Christoforidis, None.

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