Intratumoral CCR5+ neutrophils identify immunogenic subtype muscle-invasive bladder cancer with favorable prognosis and therapeutic responses

Zhuoyi Xiang; Quan Zhou; Han Zeng; Zewei Wang; Hongyu Zhang; Zhaopei Liu; Qiuren Huang; Yuan Chang; Qi Bai; Yu Xia; Yiwei Wang; Li Liu; Yu Zhu; Le Xu; Bo Dai; Jiajun Wang; Jianming Guo; Jiejie Xu

doi:10.1080/2162402X.2020.1802176

Intratumoral CCR5⁺ neutrophils identify immunogenic subtype muscle-invasive bladder cancer with favorable prognosis and therapeutic responses

Oncoimmunology. 2020 Aug 12;9(1):1802176. doi: 10.1080/2162402X.2020.1802176.

Authors

Zhuoyi Xiang¹, Quan Zhou², Han Zeng², Zewei Wang¹, Hongyu Zhang², Zhaopei Liu², Qiuren Huang², Yuan Chang³, Qi Bai¹, Yu Xia¹, Yiwei Wang⁴, Li Liu¹, Yu Zhu³, Le Xu⁵, Bo Dai³, Jiajun Wang¹, Jianming Guo¹, Jiejie Xu²

Affiliations

¹ Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.
² Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
³ Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.
⁴ Department of Urology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁵ Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Abstract

Our previous studies revealed tumor-infiltrating neutrophils (TINs) played dichotomous roles in different cancers, indicating diverse TINs subtypes might orchestrate anti-tumor immunity or immune evasion, respectively. This study aimed to investigate the clinical significance and immune characteristics of CCR5⁺TINs in muscle-invasive bladder cancer (MIBC). Two hundred and fifty-seven MIBC patients from two clinical centers and 95 fresh MIBC samples were included. CCR5⁺TINs were stained by immunohistochemistry, and the relationship between patients' clinic-pathological features and prognosis was evaluated, respectively. Immunohistochemistry and flow cytometry were applied to assess the immune features of CCR5⁺TINs and their correlations with other immune cells. In vitro study was conducted to estimate immune characteristics of CCR5⁺TINs and their predictive potential for pembrolizumab therapeutic response. In the two MIBC cohorts, we found that high CCR5⁺TINs infiltration could predict better overall survival (OS, P= .032, 0.039) and recurrence-free survival (RFS, P= .001, 0.006) and be associated with survival benefit from adjuvant chemotherapy (ACT, P< .001 for OS and P= .022 for RFS, respectively) in merely pT2N0 MIBC. Maraviroc could partly reduce IFN-γ secretion by CCR5⁺TINs (P< .001). CCR5⁺TINs correlated with higher expression of effector molecules within CD8⁺T cells. Notably, pembrolizumab treatment could only elevate the apoptosis status of tumor cells in the CCR5⁺TINs high subgroup (P < .001), other than CCR5⁺TINs low subgroup (P= .481). Our results indicate that CCR5⁺TINs could prime anti-tumor immune response through autonomous IFN-γ release, thus leading to favorable prognosis and superior therapeutic response to ACT and immunotherapy in MIBC.

Keywords: CCR5; Muscle-invasive bladder cancer; adjuvant chemotherapy; pembrolizumab; prognosis; tumor-infiltrating neutrophils.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Chemotherapy, Adjuvant
Humans
Muscles
Neutrophils
Prognosis
Receptors, CCR5 / therapeutic use
Urinary Bladder Neoplasms* / drug therapy

Substances

CCR5 protein, human
Receptors, CCR5

Grants and funding

This study was funded by grants from National Natural Science Foundation of China (31770851, 81702496, 81702497, 81702805, 81772696, 81872082, 81902556, 81902563, 81902898, 81974393), National Key R&D Program of China (2017YFC0114303), Shanghai Municipal Natural Science Foundation (16ZR1406500, 17ZR1405100, 19ZR1431800), Guide Project of Science and Technology Commission of Shanghai Municipality (17411963100), Shanghai Sailing Program (18YF1404500, 19YF1407900, 19YF1427200), Shanghai Municipal Commission of Health and Family Planning Program (20174Y0042, 201840168, 20184Y0151), Fudan University Shanghai Cancer Center for Outstanding Youth Scholars Foundation (YJYQ201802) and Shanghai Cancer Research Charity Center. All these study sponsors have no roles in the study design, in the collection, analysis and interpretation of data.