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Cancer Immunology Research
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Retinoic Acid Synthesis Deficiency Fosters the Generation of Polymorphonuclear Myeloid-Derived Suppressor Cells in Colorectal Cancer

Hong-Wei Sun, Jing Chen, Wen-Chao Wu, Yan-Yan Yang, Yi-Tuo Xu, Xing-Juan Yu, Hai-Tian Chen, Zilian Wang, Xiao-Jun Wu and Limin Zheng
Hong-Wei Sun
1Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
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  • ORCID record for Hong-Wei Sun
Jing Chen
1Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
2MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
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Wen-Chao Wu
1Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Yan-Yan Yang
1Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
2MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
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Yi-Tuo Xu
1Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
2MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
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Xing-Juan Yu
1Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
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Hai-Tian Chen
4Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
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Zilian Wang
4Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
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Xiao-Jun Wu
1Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
5Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China.
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  • For correspondence: zhenglm@mail.sysu.edu.cn wuxj@sysucc.org.cn
Limin Zheng
1Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
2MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
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  • For correspondence: zhenglm@mail.sysu.edu.cn wuxj@sysucc.org.cn
DOI: 10.1158/2326-6066.CIR-20-0389 Published January 2021
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Abstract

Metabolism is reprogrammed in cancer to fulfill the demands of malignant cells for cancer initiation and progression. Apart from its effects within cancer cells, little is known about whether and how reprogramed metabolism regulates the surrounding tumor microenvironment (TME). Myeloid-derived suppressor cells (MDSC) are key regulators of the TME and greatly affect tumor progression and therapeutic responses. In this study, our results revealed that retinol metabolism–related genes and enzymes were significantly downregulated in human colorectal cancer compared with adjacent colonic tissues, and tumors exhibited a defect in retinoic acid (RA) synthesis. Reduced ADH1-mediated retinol metabolism was associated with attenuated RA signaling and accumulated MDSCs in colorectal cancer tumors. Using an in vitro model, generating MDSCs from CD34+ myeloid precursors, we found that exogenous RA could abrogate the generation of polymorphonuclear MDSCs (PMN-MDSC) with negligible impact on myeloid differentiation. Mechanistically, RA could restrain the glycolytic capacity of myeloid cells, which in turn activated the AMP-activated protein kinase (AMPK) pathway, further impairing the suppressive capacity of myeloid cells. Supplementation with RA could significantly delay tumor growth, with reduced arginase-1–expressing myeloid cells and increased CD8+ and granzyme B+ T cells in both colitis-associated and implanted MC38 mouse colorectal cancer models. Our results indicated that the defect in ADH1-mediated RA synthesis could provide a possible mechanism that fosters the generation of PMN-MDSCs in colorectal cancer and that restoring RA signaling in the TME could serve as a promising therapeutic strategy to abrogate the generation of PMN-MDSCs.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Cancer Immunol Res 2021;9:20–33

  • Received May 8, 2020.
  • Revision received September 8, 2020.
  • Accepted November 5, 2020.
  • Published first November 11, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Immunology Research: 9 (1)
January 2021
Volume 9, Issue 1
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Retinoic Acid Synthesis Deficiency Fosters the Generation of Polymorphonuclear Myeloid-Derived Suppressor Cells in Colorectal Cancer
Hong-Wei Sun, Jing Chen, Wen-Chao Wu, Yan-Yan Yang, Yi-Tuo Xu, Xing-Juan Yu, Hai-Tian Chen, Zilian Wang, Xiao-Jun Wu and Limin Zheng
Cancer Immunol Res January 1 2021 (9) (1) 20-33; DOI: 10.1158/2326-6066.CIR-20-0389

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Retinoic Acid Synthesis Deficiency Fosters the Generation of Polymorphonuclear Myeloid-Derived Suppressor Cells in Colorectal Cancer
Hong-Wei Sun, Jing Chen, Wen-Chao Wu, Yan-Yan Yang, Yi-Tuo Xu, Xing-Juan Yu, Hai-Tian Chen, Zilian Wang, Xiao-Jun Wu and Limin Zheng
Cancer Immunol Res January 1 2021 (9) (1) 20-33; DOI: 10.1158/2326-6066.CIR-20-0389
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