为了提高免疫检查点阻断（ICB）治疗的疗效，与抗癌疗法结合使用多种抗癌疗法。组织损伤的发生很常见，会引发多种炎症性细胞因子的产生。胃肠道器官是常见的受影响部位。我们调查了急性结肠炎对抗原特异性CD8+细胞毒性T淋巴细胞（CTL）对肿瘤浸润、控制肿瘤生长和对PD-1抗体（抗-PD-1）的反应的影响。多种肿瘤细胞系被皮下或肝内接种到同种系小鼠体内。当肿瘤块形成时，激活的CTL被静脉转移至承载肿瘤的小鼠体内，并饮用含2％硫酸葡聚糖（DSS）的饮水诱导急性结肠炎。研究了肿瘤生长、两种耗竭的CTL亚群的浸润情况以及CTL与肿瘤内血管内皮细胞的相互作用。 急性结肠炎降低了CTL介导的抗肿瘤效应，与炎症肠道中IL-17A的升高相关。在肿瘤床中，被定义为PD-1+Slamf6+Tim3-的干细胞样耗竭CTL表达了更高水平的IL-17A受体异二聚体和较低水平的白细胞功能相关抗原-1（LFA-1），而被定义为PD-1+Slamf6-Tim3+的末端耗竭CTL没有表达这些特征。IL-17A刺激降低了干细胞样耗竭CTL上的LFA-1表面表达，并降低了肿瘤内血管内皮细胞上的内皮细胞黏附分子-1（ICAM-1）的表达。IL-17A刺激抑制了穿越肿瘤内血管内皮细胞的越界和干细胞样耗竭CTL的自我更新。给结肠炎小鼠注射抗IL-17A中和抗体可恢复CTL对肿瘤的浸润并增强抗PD-1治疗对肿瘤的疗效。在接受抗PD-1和抗血管内皮生长因子抗体联合治疗的33例肝细胞癌患者中，其中15例患者病情恶化，其血清IL-17A在治疗后24小时与治疗前相比增加，与18例患者相比，这些患者的血清IL-17A未增加。 异常产生的IL-17A主要抑制了干细胞样耗竭CTL对肿瘤的浸润。当由于组织损伤（如急性结肠炎）引起治疗相关的IL-17A升高时，通过给予抗IL-17A可以提高ICB基于免疫治疗的疗效。© 2023年。BioMed Central Ltd.，Springer Nature的一部分。

Variated anti-cancer therapies are combined with immune checkpoint blockades (ICBs) for improving ICB therapeutic efficacy. Occurrence of tissue damage is common that triggers multiple inflammatory cytokine generation. Gastrointestinal organs are the commonly affected. We investigated the impact of acute colitis on tumor infiltration of antigen-specific CD8+ cytotoxic T lymphocytes (CTLs) for controlling tumor growth and responding to antibody against PD-1 (anti-PD-1).Several tumor cell lines were inoculated into syngeneic mice subcutaneously or intra-hepatically. When tumor mass formed, activated CTLs were intravenously transferred into the tumor-bearing mice, that were given the drinking water containing 2% dextran sulfate sodium (DSS) for acute colitis induction. Tumor growth, infiltration of two exhausted CTL subsets, and the CTL interaction with tumor vascular endothelium were examined.Acute colitis dampened CTL-mediated antitumor effects, correlating with IL-17A elevation in the inflamed intestine. In the tumor bed, stem-like exhausted CTLs, which were defined as PD-1+Slamf6+Tim3-, expressed higher IL-17A receptor heterodimers and lower leukocyte function-associated antigen-1 (LFA-1) than terminally exhausted CTLs did, that were defined as PD-1+Slamf6-Tim3+. IL-17A stimulation reduced LFA-1 surface expression on stem-like exhausted CTLs and the counterpart ICAM-1 (intracellular adhesion molecule-1) on tumor vascular endothelium. IL-17A stimulation suppressed the extravasation across tumor vascular endothelium and self-renewal of stem-like, not the terminally exhausted CTLs. Administration of anti-IL-17A neutralizing antibody to the colitis mice restored the CTL tumor infiltration and enhanced anti-PD-1 treatment efficacy against tumors. In 33 hepatocellular carcinoma patients being treated with anti-PD-1 plus antibody against vascular endothelial growth factor, disease progression of 15 patients, that exhibited serum IL-17A increase 24 h post-therapy as compared to pre-therapy level, was poorer than that of 18 patients that exhibited serum IL-17A no-increase.Abnormal generation of IL-17A mainly repressed tumor infiltration of stem-like exhausted CTLs. ICB-based immunotherapeutic efficacy could be upgraded with administration of anti-IL-17A, when treatment-related IL-17A elevation occurred due to tissue damage, such as acute colitis.© 2023. BioMed Central Ltd., part of Springer Nature.