Tumor-associated Macrophage-derived Interleukin-23 Interlinks Kidney Cancer Glutamine Addiction with Immune Evasion.
Abstract | BACKGROUND: 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 1α (HIF1α). IL-23 activates regulatory T-cell proliferation and promotes IL-10 and transforming growth factor β 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: PATIENT SUMMARY:
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Authors | Qiang Fu, Le Xu, Yiwei Wang, Qi Jiang, Zheng Liu, Junyu Zhang, Quan Zhou, Han Zeng, Shanyou Tong, Tao Wang, Yangyang Qi, Baoying Hu, Hangcheng Fu, Huyang Xie, Lin Zhou, Yuan Chang, Yu Zhu, Bo Dai, Weijuan Zhang, Jiejie Xu |
Journal | European urology
(Eur Urol)
Vol. 75
Issue 5
Pg. 752-763
(05 2019)
ISSN: 1873-7560 [Electronic] Switzerland |
PMID | 30293904
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved. |
Chemical References |
- Antibodies
- HIF1A protein, human
- Hypoxia-Inducible Factor 1, alpha Subunit
- Interleukin-23
- Glutamine
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Topics |
- Animals
- Antibodies
(therapeutic use)
- Carcinoma, Renal Cell
(genetics, immunology, metabolism, therapy)
- Cell Proliferation
(drug effects)
- Cells, Cultured
- Gene Ontology
- Glutamine
(metabolism)
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit
(metabolism)
- Immune Evasion
- Immune Tolerance
(drug effects)
- Interleukin-23
(antagonists & inhibitors, immunology, metabolism, pharmacology)
- Kidney Neoplasms
(genetics, immunology, metabolism, therapy)
- Lymphocyte Activation
- Macrophages
(metabolism)
- Mice
- Oncogene Addiction
- Survival Rate
- T-Lymphocytes, Regulatory
(immunology, physiology)
- Tumor Escape
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