Immunosuppressive tumor-associated macrophages expressing interlukin-10 conferred poor prognosis and therapeutic vulnerability in patients with muscle-invasive bladder cancer

Yijia Xu; Han Zeng; Kaifeng Jin; Zhaopei Liu; Yu Zhu; Le Xu; Zewei Wang; Yuan Chang; Jiejie Xu

doi:10.1136/jitc-2021-003416

Immunosuppressive tumor-associated macrophages expressing interlukin-10 conferred poor prognosis and therapeutic vulnerability in patients with muscle-invasive bladder cancer

J Immunother Cancer. 2022 Mar;10(3):e003416. doi: 10.1136/jitc-2021-003416.

Authors

Yijia Xu^#¹, Han Zeng^#¹, Kaifeng Jin^#¹, Zhaopei Liu^#¹, Yu Zhu², Le Xu³, Zewei Wang⁴, Yuan Chang⁵, Jiejie Xu⁶

Affiliations

¹ Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
² Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.
³ Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴ Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China zwwang12@fudan.edu.cn changyuan0802@163.com jjxufdu@fudan.edu.cn.
⁵ Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China zwwang12@fudan.edu.cn changyuan0802@163.com jjxufdu@fudan.edu.cn.
⁶ Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China zwwang12@fudan.edu.cn changyuan0802@163.com jjxufdu@fudan.edu.cn.

^# Contributed equally.

Abstract

Background: Tumor-associated macrophages (TAMs) secreting IL-10 could be a specific functional cell subset with distinct polarization state and suppressive role in antitumor immune response. Here, we assessed the associations of clinical outcome, therapeutic responses and molecular features with IL-10⁺TAMs infiltration, and potential impact of IL-10⁺TAMs on the immune contexture in muscle-invasive bladder cancer (MIBC).

Methods: In this retrospective study, 128 patients and 391 patients with MIBC from Zhongshan hospital (ZS cohort) and The Cancer Genome Atlas cohort were included respectively. Immunohistochemistry was performed to quantify various immune cell infiltration in the ZS cohort. Single cell RNA sequencing and flow cytometry were performed to examine the functional status of IL-10⁺TAMs and its correlation with other immune cells. Survival analyses and assessment of the adjuvant chemotherapy (ACT) benefit analyses were also performed.

Results: High IL-10⁺TAMs infiltration was associated with inferior prognosis in terms of overall survival and recurrence-free survival, but superior chemotherapeutic response in MIBC. IL-10⁺TAMs with suppressive features were associated with immunoevasive tumor microenviroment characterized by exhausted CD8⁺ T cells, immature NK cells and increased immune checkpoint expression. Additionally, high IL-10⁺TAMs infiltration showed a strong linkage with basal-featured subtype and augmented EGF signaling.

Conclusions: Immunosuppresive IL-10⁺TAMs contributed to an evasive contexture with incapacitated immune effector cells and increased immune checkpoint expression, therefore, predicting unfavorable clinical outcomes despite better ACT responsiveness. IL-10⁺TAMs might provide guidance for customized selection of EGFR-targeted therapy, FGFR3-targeted therapy as well as immunotherapy. The potential of immunosuppressive IL-10⁺TAMs as a therapeutic target is worth further exploration.

Keywords: immunotherapy; macrophages; tumor biomarkers; tumor microenvironment; urinary bladder neoplasms.

Publication types

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

MeSH terms

CD8-Positive T-Lymphocytes
Humans
Interleukin-10* / genetics
Muscles / pathology
Prognosis
Retrospective Studies
Tumor-Associated Macrophages
Urinary Bladder Neoplasms* / drug therapy
Urinary Bladder Neoplasms* / genetics

Substances

Interleukin-10