Melese Etienne S, Franks Elizabeth, Cederberg Rachel A, Harbourne Bryant T, Shi Rocky, Wadsworth Brennan J, Collier Jenna L, Halvorsen Elizabeth C, Johnson Fraser, Luu Jennifer, Oh Min Hee, Lam Vivian, Krystal Gerald, Hoover Shelley B, Raffeld Mark, Simpson R Mark, Unni Arun M, Lam Wan L, Lam Stephen, Abraham Ninan, Bennewith Kevin L, Lockwood William W
Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.
Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC, Canada.
Oncoimmunology. 2021 Dec 30;11(1):2010905. doi: 10.1080/2162402X.2021.2010905. eCollection 2022.
Current immunotherapies for lung cancer are only effective in a subset of patients. Identifying tumor-derived factors that facilitate immunosuppression offers the opportunity to develop novel strategies to supplement and improve current therapeutics. We sought to determine whether expression of driver oncogenes in lung cancer cells affects cytokine secretion, alters the local immune environment, and influences lung tumor progression. We demonstrate that oncogenic EGFR and KRAS mutations, which are early events in lung tumourigenesis, can drive cytokine and chemokine production by cancer cells. One of the most prominent changes was in CCL5, which was rapidly induced by KRAS or EGFR expression, through MAPK activation. Immunocompetent mice implanted with syngeneic KRAS-mutant lung cancer cells deficient in CCL5 have decreased regulatory T cells (T), evidence of T cell exhaustion, and reduced lung tumor burden, indicating tumor-cell CCL5 production contributes to an immune suppressive environment in the lungs. Furthermore, high expression correlates with poor prognosis, immunosuppressive regulatory T cells, and alteration to CD8 effector function in lung adenocarcinoma patients. Our data support targeting CCL5 or CCL5 receptors on immune suppressive cells to prevent formation of an immune suppressive tumor microenvironment that promotes lung cancer progression and immunotherapy insensitivity.
目前用于肺癌的免疫疗法仅对一部分患者有效。识别促进免疫抑制的肿瘤衍生因子为开发补充和改进现有疗法的新策略提供了机会。我们试图确定肺癌细胞中驱动癌基因的表达是否会影响细胞因子分泌、改变局部免疫环境并影响肺肿瘤进展。我们证明，致癌性EGFR和KRAS突变作为肺肿瘤发生的早期事件，可驱动癌细胞产生细胞因子和趋化因子。最显著的变化之一是CCL5，它通过MAPK激活由KRAS或EGFR表达迅速诱导产生。植入缺乏CCL5的同基因KRAS突变肺癌细胞的免疫活性小鼠，其调节性T细胞减少，有T细胞耗竭的迹象，肺肿瘤负担减轻，这表明肿瘤细胞产生的CCL5有助于肺部形成免疫抑制环境。此外，高表达与肺腺癌患者的预后不良、免疫抑制性调节性T细胞以及CD8效应功能改变相关。我们的数据支持靶向免疫抑制细胞上的CCL5或CCL5受体，以防止形成促进肺癌进展和免疫治疗不敏感的免疫抑制性肿瘤微环境。
