iNKT细胞-中性粒细胞交流促进结直肠癌发病机制。
iNKT cell-neutrophil crosstalk promotes colorectal cancer pathogenesis.
发表日期：2023 Mar 31
作者：
Georgia Lattanzi, Francesco Strati, Angélica Díaz-Basabe, Federica Perillo, Chiara Amoroso, Giulia Protti, Maria Rita Giuffrè, Luca Iachini, Alberto Baeri, Ludovica Baldari, Elisa Cassinotti, Michele Ghidini, Barbara Galassi, Gianluca Lopez, Daniele Noviello, Laura Porretti, Elena Trombetta, Eleonora Messuti, Luca Mazzarella, Giandomenica Iezzi, Francesco Nicassio, Francesca Granucci, Maurizio Vecchi, Flavio Caprioli, Federica Facciotti
来源：
Mucosal Immunology
摘要：
iNKT细胞在肠道内占领一个重要的效应性T细胞比例，并被认为是癌症免疫治疗的一个有吸引力的平台。尽管iNKT细胞是细胞毒性淋巴细胞，但它们在结肠直肠癌（CRC）中的功能角色仍然存在争议，限制了它们的治疗用途。为了了解iNKT细胞在CRC中的作用，我们检查了患者（n = 118）和不同鼠模型的CRC病变的免疫细胞组成和iNKT细胞表型。高维单细胞流式细胞术、宏基因组学和RNAseq实验揭示了iNKT细胞在肿瘤病变中的富集。与肿瘤相关的致病微生物Fusobacterium nucleatum会诱导iNKT细胞中的IL17和GM-CSF表达，但不影响它们的细胞毒性能力，而是促进iNKT介导的类PMN-MDSCs神经粒性粒细胞的招募和功能。缺乏iNKT细胞会降低肿瘤负担和免疫抑制性中性粒细胞的招募。αGalCer诱导iNKT细胞在体内激活，恢复了它们的抗肿瘤功能，表明可以调节iNKT细胞以克服CRC相关的免疫逃逸。iNKT细胞和中性粒细胞的肿瘤共浸润与负面临床结果相关，强调了iNKT细胞在CRC病理生理学中的重要性。我们的结果揭示了iNKT细胞在CRC中的功能可塑性，表明iNKT细胞在塑造TME方面具有重要的意义及治疗方面的相关性。版权所有©2023作者。Elsevier Inc.保留所有权利。
iNKT cells account for a relevant fraction of effector T-cells in the intestine and are considered an attractive platform for cancer immunotherapy. Although iNKT cells are cytotoxic lymphocytes, their functional role in colorectal cancer (CRC) is still controversial, limiting their therapeutic use. To gain insights into iNKT cells role in CRC we examined the immune cell composition and iNKT cell phenotype of CRC lesions in patients (n=118) and different murine models. High-dimensional single-cell flow cytometry, metagenomics and RNAseq experiments revealed that iNKT cells are enriched in tumor lesions. The tumor-associated pathobiont Fusobacterium nucleatum induces IL17 and GM-CSF expression in iNKT cells without affecting their cytotoxic capability but promoting iNKT-mediated recruitment of neutrophils with PMN-MDSCs-like phenotype and functions. Lack of iNKT cells reduced tumor burden and recruitment of immune suppressive neutrophils. iNKT cells in vivo activation with αGalCer restored their anti-tumor function suggesting that iNKT cells can be modulated to overcome CRC-associated immune evasion. Tumor co-infiltration by iNKT cells and neutrophils correlates with negative clinical outcomes highlighting the importance of iNKT cells in the pathophysiology of CRC. Our results reveal a functional plasticity of iNKT cells in CRC suggesting a pivotal role of iNKT cells in shaping the TME with relevant implications for treatment.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.