Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.
J Immunother Cancer. 2022 Mar;10(3). doi: 10.1136/jitc-2021-003416.
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-10TAMs infiltration, and potential impact of IL-10TAMs on the immune contexture in muscle-invasive bladder cancer (MIBC).
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-10TAMs and its correlation with other immune cells. Survival analyses and assessment of the adjuvant chemotherapy (ACT) benefit analyses were also performed.
High IL-10TAMs infiltration was associated with inferior prognosis in terms of overall survival and recurrence-free survival, but superior chemotherapeutic response in MIBC. IL-10TAMs 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-10TAMs infiltration showed a strong linkage with basal-featured subtype and augmented EGF signaling.
Immunosuppresive IL-10TAMs 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-10TAMs might provide guidance for customized selection of EGFR-targeted therapy, FGFR3-targeted therapy as well as immunotherapy. The potential of immunosuppressive IL-10TAMs as a therapeutic target is worth further exploration.
肿瘤相关巨噬细胞（TAMs）分泌的 IL-10 可能是一种具有独特极化状态和抑制抗肿瘤免疫反应功能的特定功能细胞亚群。在这里，我们评估了临床结局、治疗反应和分子特征与 IL-10TAMs 浸润的相关性，以及 IL-10TAMs 对肌层浸润性膀胱癌（MIBC）免疫微环境的潜在影响。
在这项回顾性研究中，我们纳入了来自中山医院（ZS 队列）的 128 例和癌症基因组图谱队列的 391 例 MIBC 患者。我们通过免疫组织化学方法对 ZS 队列中的各种免疫细胞浸润进行了定量分析。我们通过单细胞 RNA 测序和流式细胞术检测了 IL-10TAMs 的功能状态及其与其他免疫细胞的相关性。我们还进行了生存分析和辅助化疗（ACT）获益分析。
高 IL-10TAMs 浸润与总生存和无复发生存的预后不良相关，但与 MIBC 的化疗反应良好相关。具有抑制作用的 IL-10TAMs 与具有耗竭性 CD8 T 细胞、不成熟 NK 细胞和增加免疫检查点表达的免疫逃避肿瘤微环境特征相关。此外，高 IL-10TAMs 浸润与基底样特征亚型和增强的 EGF 信号密切相关。
抑制性 IL-10TAMs 导致了具有失能免疫效应细胞和增加免疫检查点表达的逃避结构，因此尽管 ACT 反应良好，但预测预后不良。IL-10TAMs 可能为 EGFR 靶向治疗、FGFR3 靶向治疗以及免疫治疗的个体化选择提供指导。抑制性 IL-10TAMs 作为治疗靶点的潜力值得进一步探索。
