Poor clinical outcomes and immunoevasive contexture in interleukin-9 abundant muscle-invasive bladder cancer.

Chemotherapy and immunotherapy yield survival benefits for muscle-invasive bladder cancer (MIBC) patients, in which tumor microenvironment has been found to exert crucial roles through tipping the balance between anti-tumor immunity and immune evasion. This study aims to explore the clinical significance and therapeutic role of intratumoral interleukin-9-producing cells (IL-9+ cells) in MIBC. 259 MIBC patients from two independent clinic centers were utilized for retrospective analysis in the study. 65 fresh MIBC tumor tissues were used to evaluate the infiltration and function of immune cells via flow cytometry and ex vivo intervention experiments. 391 MIBC patients of TCGA were applied for bioinformatics analysis. It was found that patients with high IL-9+ cells infiltration had worse overall survival and relapse free survival. pT2 patients with low IL-9+ cells infiltration could benefit more from adjuvant chemotherapy (ACT). IL-9+ cells infiltration was correlated with decreased expression of granzyme B from CD8+ T cells and NK cells and perforin from CD8+ T cells, while blockade of IL-9 reactivated the anti-tumor capacity of both cells leading to tumor regression. Furthermore, IL-9+ cells infiltration could be a biomarker for predicting anti-PD-1 efficacy. In conclusion, IL-9+ cells infiltration could be applied as an independent prognosticator for clinical outcome and ACT/anti-PD-1 effectiveness. IL-9+ cells infiltration diminished the cytotoxicity of CD8+ T cells and NK cells resulting in tumor immune evasion, thus targeting IL-9 could be a potential therapeutic strategy for MIBC. This article is protected by copyright. All rights reserved.

International journal of cancer. 2020 Jul 31 [Epub ahead of print]

Quan Zhou, Hongyu Zhang, Zewei Wang, Han Zeng, Zhaopei Liu, Qiuren Huang, Zhiyuan Lin, Yang Qu, Ying Xiong, Jiajun Wang, Yuan Chang, Qi Bai, Yu Xia, Yiwei Wang, Li Liu, Bo Dai, Jianming Guo, Yu Zhu, Le Xu, Jiejie Xu

Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China., Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China., Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China., Department of Urology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.