PT  - JOURNAL ARTICLE
AU  - Sun, Hong-Wei
AU  - Chen, Jing
AU  - Wu, Wen-Chao
AU  - Yang, Yan-Yan
AU  - Xu, Yi-Tuo
AU  - Yu, Xing-Juan
AU  - Chen, Hai-Tian
AU  - Wang, Zilian
AU  - Wu, Xiao-Jun
AU  - Zheng, Limin
TI  - Retinoic acid synthesis deficiency fosters the generation of polymorphonuclear myeloid-derived suppressor cells in colorectal cancer
AID  - 10.1158/2326-6066.CIR-20-0389
DP  - 2020 Jan 01
TA  - Cancer Immunology Research
PG  - canimm.0389.2020
4099  - http://cancerimmunolres.aacrjournals.org/content/early/2020/11/11/2326-6066.CIR-20-0389.short
4100  - http://cancerimmunolres.aacrjournals.org/content/early/2020/11/11/2326-6066.CIR-20-0389.full
AB  - Metabolism is reprogrammed in cancer to fulfill the demands of malignant cells for cancer initiation and progression. Apart from their effects within cancer cells, little is known about whether and how reprogramed metabolism regulates the surrounding tumor microenvironment (TME). Myeloid-derived suppressor cells (MDSCs) are key regulators of the TME and greatly impact 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 (CRC) compared to 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 CRC tumors. Using an in vitro model, generating MDSCs from CD34P+P myeloid precursors, we found that exogenous RA could abrogate the generation of polymorphonuclear MDSCs (PMN-MDSCs) 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, increased CD8P+P and granzyme BP+P T cells in both colitis-associated and implanted MC38 mouse CRC 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 CRC and that restoring RA signaling in the TME could serve as a promising therapeutic strategy to abrogate the generation of PMN-MDSCs.