Hypoxia inducible factor HIF-1 promotes myeloid-derived suppressor cells accumulation through ENTPD2/CD39L1 in hepatocellular carcinoma

Abstract

Myeloid-derived suppressor cells (MDSCs) possess immunosuppressive activities, which allow cancers to escape immune surveillance and become non-responsive to immune checkpoints blockade. Here we report hypoxia as a cause of MDSC accumulation. Using hepatocellular carcinoma (HCC) as a cancer model, we show that hypoxia, through stabilization of hypoxia-inducible factor-1 (HIF-1), induces ectoenzyme, ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2/CD39L1), in cancer cells, causing its overexpression in HCC clinical specimens. Overexpression of ENTPD2 is found as a poor prognostic indicator for HCC. Mechanistically, we demonstrate that ENTPD2 converts extracellular ATP to 5′-AMP, which prevents the differentiation of MDSCs and therefore promotes the maintenance of MDSCs. We further find that ENTPD2 inhibition is able to mitigate cancer growth and enhance the efficiency and efficacy of immune checkpoint inhibitors. Our data suggest that ENTPD2 may be a good prognostic marker and therapeutic target for cancer patients, especially those receiving immune therapy.

Fusobacterium nucleatum and colorectal cancer: A mechanistic overview

“…Hashemi Goradel et al, 2017). Consistent with this proposal, Mendes (Chiu et al, 2017). It has been shown that MDSCs reduce infiltration of T cell into tumor (Highfill et al, 2014), increase matrix metalloproteinase 9, which increases angiogenesis (L. Yang et al, 2004), and maintains stemness characteristics (Cui et al, 2013).…”

Significant antitumor effect of an antibody against TMEM180, a new colorectal cancer‐specific molecule

“…More importantly, anti-TMEM180 mAb had in vitro ADCC and In further experiments, we found that the TMEM180 gene had 10 hypoxia response element consensus sequences, which may be HIF-1α binding sites controlled by hypoxia. 22,23,33 Recent studies have indicated that not only hypoxia but also chemotherapy induces HIF-1α expression followed by T-cell anergy and increased dissemination of cancer cells. 34 HIF-1α is currently considered a key factor of cancer stem cell function.…”

Anemia management in cancer patients with chronic kidney disease

“…This complex acts as a transcriptional factor for hundreds of genes involved in angiogenesis, including vascular endothelial growth factor (VEGF), platelet‐derived growth factor (PDGF), and angiopoietin‐1 (ANGPT1) . In addition to regulating the expression of genes involved with tumor growth, invasion, and metastasis, the HIF pathway plays a key role in the development of resistance to anti‐cancer therapies and HIF‐1α facilitates escape of tumor cells from T‐cell recognition …”

“…65 In addition to regulating the expression of genes involved with tumor growth, invasion, and metastasis, 66 the HIF pathway plays a key role in the development of resistance to anti-cancer therapies 67 and HIF-1α facilitates escape of tumor cells from T-cell recognition. 68 Increased HIF expression in a range of human cancers is associated with poorer prognosis and outcomes. 69 It remians unclear if HIF is acting as a tumor promoter or if higher HIF levels just reflect a more hypoxic milieu in faster growing and more aggressive tumors.…”