Tumor-associated Macrophage-derived Interleukin-23 Interlinks Kidney Cancer Glutamine Addiction with Immune Evasion
Tumor-associated Macrophage-derived Interleukin-23 Interlinks Kidney Cancer Glutamine Addiction with Immune Evasion
复制标题
肿瘤相关巨噬细胞衍生的白细胞介素 23 将肾癌谷氨酰胺成瘾与免疫逃避联系起来
DOI：
10.1016/j.eururo.2018.09.030
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发表时间：
2019-05-01
期刊：
影响因子：
23.4
通讯作者：
Xu, Jiejie
中科院分区：
文献类型：
--
作者：
Fu, Qiang;Xu, Le;Xu, Jiejie
背景资料：谷氨酰胺成瘾是透明细胞肾细胞癌（ccRCC）的标志;但谷氨酰胺代谢是否影响局部免疫监视尚不清楚。目的：寻找谷氨酰胺成瘾的ccRCC的潜在治疗靶点。设计、设置和参与者：分析来自上海队列的ccRCC患者的肿瘤和来自癌症基因组图谱（TCGA）队列的ccRCC肿瘤数据。用新鲜的人ccRCC肿瘤和小鼠肿瘤细胞进行体内和体外研究。结果测量和统计分析：通过流式细胞术分析免疫细胞的数量和功能。测定谷氨酰胺和细胞因子浓度。使用Kaplan-Meier和考克斯回归分析比较不同亚群患者的生存率。结果和局限性：我们发现在ccRCC中，高白细胞介素（IL）-23表达与TCGA和CCGA中的不良生存率显著相关。（总生存期[OS]风险比[HR] = 2.04，癌症特异性生存期[CSS] HR = 2.95;所有p < 0.001）和上海（OS HR = 2.07，CSS HR = 3.92;所有p < 0.001）队列。IL-23阻断降低荷瘤小鼠的存活率，促进人ccRCC肿瘤的体外培养物中的T细胞细胞毒性，并增强抗PD-1抗体的治疗益处。从机制上讲，ccRCC肿瘤细胞的谷氨酰胺消耗导致细胞外谷氨酰胺的局部剥夺，这通过缺氧诱导因子1 α（HIF 1 α）的活化诱导肿瘤浸润性巨噬细胞分泌IL-23。IL-23激活调节性T细胞增殖并促进IL-10和转化生长因子β表达，从而抑制细胞毒性淋巴细胞对肿瘤细胞的杀伤。在TCGA队列和上海ccRCC患者的肿瘤中证实了谷氨酰胺代谢、IL-23水平和Treg反应之间的正相关性。研究的局限性包括谷氨酰胺剥夺和IL-23对其他免疫细胞的影响尚不清楚。结论：巨噬细胞分泌的IL-23增强了谷氨酰胺成瘾肿瘤中的Treg功能;因此，IL-23是ccRCC免疫治疗的一个有前途的靶点。在本研究中，我们分析了谷氨酰胺依赖性肾透明细胞癌（ccRCC）的免疫成分，来自两个患者群组的肿瘤，并进行体外和体内研究。我们发现ccRCC肿瘤细胞内在的谷氨酰胺代谢通过白细胞介素（IL）-23协调免疫逃避，IL-23高水平患者的生存率明显低于IL-23低水平患者。因此，IL-23应被视为ccRCC的治疗靶点，无论是单独使用还是与免疫检查点抑制剂联合使用。(C)2018年欧洲泌尿外科协会。Elsevier B. V.出版，保留所有权利。
Background: Glutamine addiction is a hallmark of clear cell renal cell carcinoma (ccRCC); yet whether glutamine metabolism impacts local immune surveillance is unclear. This knowledge may yield novel immunotherapeutic opportunities.Objective: To seek a potential therapeutic target in glutamine-addicted ccRCC.Design, setting, and participants: Tumors from ccRCC patients from a Shanghai cohort and ccRCC tumor data from The Cancer Genome Atlas (TCGA) cohort were analyzed. In vivo and in vitro studies were conducted with fresh human ccRCC tumors and murine tumor cells.Outcome measurements and statistical analysis: Immune cell numbers and functions were analyzed by flow cytometry. Glutamine and cytokine concentrations were determined. Survival was compared between different subpopulations of patients using Kaplan-Meier and Cox regression analyses.Results and limitations: We found that in ccRCC, high interleukin (IL)-23 expression was significantly associated with poor survival in both TCGA (overall survival [OS] hazard ratio [HR] = 2.04, cancer-specific survival [CSS] HR = 2.95; all p < 0.001) and Shanghai (OS HR = 2.07, CSS HR = 3.92; all p < 0.001) cohorts. IL-23 blockade prolongs the survival of tumor-bearing mice, promotes T-cell cytotoxicity in in vitro cultures of human ccRCC tumors, and augments the therapeutic benefits of anti-PD-1 antibodies. Mechanistically, glutamine consumption by ccRCC tumor cells results in the local deprivation of extracellular glutamine, which induces IL-23 secretion by tumor-infiltrating macrophages via the activation of hypoxia-inducible factor 1 alpha (HIF1 alpha). IL-23 activates regulatory T-cell proliferation and promotes IL-10 and transforming growth factor beta expression, thereby suppressing tumor cell killing by cytotoxic lymphocytes. The positive correlations between glutamine metabolism, IL-23 levels, and Treg responses are confirmed in both TCGA cohort and tumors from Shanghai ccRCC patients. Study limitations include the unclear impacts of glutamine deprivation and IL-23 on other immune cells.Conclusions: Macrophage-secreted IL-23 enhanced Treg functions in glutamine-addicted tumors; thus, IL-23 is a promising target for immunotherapy in ccRCC.Patient summary: In this study, we analyzed the immune components in glutamine-addicted clear cell renal cell carcinoma (ccRCC) tumors from two patient cohorts and conducted both in vitro and in vivo studies. We found that ccRCC tumor cell-intrinsic glutamine metabolism orchestrates immune evasion via interleukin (IL)-23, and IL-23high patients had significantly poorer survival than IL-23-low patients. IL-23 should thus be considered a therapeutic target in ccRCC, either alone or in combination with immune checkpoint inhibitors. (C) 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.