Poor Clinical Outcomes and Immunoevasive Contexture in Intratumoral IL-10-Producing Macrophages Enriched Gastric Cancer Patients.

IF 7.5 1区医学 Q1 SURGERY

Annals of surgery Pub Date : 2022-04-01 DOI:10.1097/SLA.0000000000004037

Hongyu Zhang, Ruochen Li, Yifan Cao, Yun Gu, Chao Lin, Xin Liu, Kunpeng Lv, Xudong He, Hanji Fang, Kaifeng Jin, Yuchao Fei, Yifan Chen, Jieti Wang, Hao Liu, He Li, Heng Zhang, Hongyong He, Weijuan Zhang

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引用次数: 80

Abstract

Objective: To investigate the clinical significance of IL-10+ tumor-associated macrophages (TAMs) in gastric cancer.

Background: Due to the plasticity and diversity of TAMs, it is necessary to phenotypically and functionally classify subsets of TAMs to better understand the critical role of TAMs in cancer progression. TAMs expressing interleukin-10 (IL-10) have been found to facilitate immune evasion in many malignancies, but the role of IL-10+ TAMs in gastric cancer remains obscure.

Methods: Four hundred and sixty-eight tumor tissue microarray specimens, 52 fresh tumor tissue samples of gastric cancer patients from Zhongshan Hospital, and data of 298 gastric cancer patients from the Cancer Genome Atlas (TCGA) were analyzed. IL-10+ TAM level and immune contexture were examined by CIBERSORT, immunohistochemistry, and flow cytometry. Clinical outcomes were analyzed by Kaplan-Meier curves and Cox model.

Results: Gastric cancer patients with high IL-10+ TAM infiltration exhibited poor prognosis and inferior therapeutic responsiveness to fluorouracil-based adjuvant chemotherapy. IL-10+ TAM infiltration yielded an immunoevasive tumor microenvironment featured by regulatory T cell infiltration and CD8+ T cell dysfunction. The combinational analysis of IL-10+ TAM and CD8+ T cell infiltration stratified patients into distinct risk groups with different clinical outcomes. Moreover, IL-10+ TAM infiltration was correlated with tumor-intrinsic characteristics including EBV status, PD-L1 expression, and genome stability in gastric cancer.

Conclusions: This study revealed that IL-10+ TAMs might drive an immunoevasive microenvironment and determine poor prognosis and inferior therapeutic responsiveness to fluorouracil-based adjuvant chemotherapy, indicating IL-10+ TAMs could be applied as a potential target for immunotherapeutic approach in gastric cancer.

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肿瘤内产生il -10巨噬细胞富集的胃癌患者的不良临床结果和免疫逃避情况。

目的:探讨IL-10+肿瘤相关巨噬细胞(tumor-associated macrophages, tam)在胃癌中的临床意义。背景:由于tam的可塑性和多样性，有必要对tam的亚群进行表型和功能分类，以更好地了解tam在癌症进展中的关键作用。表达白细胞介素-10 (IL-10)的tam在许多恶性肿瘤中促进免疫逃避，但IL-10+ tam在胃癌中的作用尚不清楚。方法:对468例肿瘤组织芯片标本、52例中山医院胃癌患者新鲜肿瘤组织标本和298例胃癌患者肿瘤基因组图谱(TCGA)数据进行分析。采用CIBERSORT、免疫组织化学和流式细胞术检测IL-10+ TAM水平和免疫情况。采用Kaplan-Meier曲线和Cox模型分析临床结果。结果:高IL-10+ TAM浸润的胃癌患者预后较差，对氟尿嘧啶辅助化疗的治疗反应性较差。IL-10+ TAM浸润形成以调节性T细胞浸润和CD8+ T细胞功能障碍为特征的免疫逃避肿瘤微环境。IL-10+ TAM和CD8+ T细胞浸润的联合分析将患者分为不同的危险组，临床结局不同。此外，IL-10+ TAM浸润与胃癌中EBV状态、PD-L1表达和基因组稳定性等肿瘤固有特征相关。结论:本研究揭示IL-10+ tam可能驱动免疫逃避微环境，导致患者对氟尿嘧啶辅助化疗预后差、治疗反应性差，提示IL-10+ tam可作为胃癌免疫治疗的潜在靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Annals of surgery 医学-外科

CiteScore

14.40

自引率

4.40%

发文量

687

审稿时长

4 months

期刊介绍： The Annals of Surgery is a renowned surgery journal, recognized globally for its extensive scholarly references. It serves as a valuable resource for the international medical community by disseminating knowledge regarding important developments in surgical science and practice. Surgeons regularly turn to the Annals of Surgery to stay updated on innovative practices and techniques. The journal also offers special editorial features such as "Advances in Surgical Technique," offering timely coverage of ongoing clinical issues. Additionally, the journal publishes monthly review articles that address the latest concerns in surgical practice.