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.
Highlights
Myeloid-derived suppressor cells (MDSCs) possess immunosuppressive activities, which allow cancers to escape immune surveillance and become non-responsive to immune checkpoints blockade
We have further demonstrated that MDSCs are attracted to tumors through CCL26, whose expression is tightly orchestrated by HIFs17
Using hepatocellular carcinoma (HCC) as a model, we previously demonstrated hypoxia as a central driver for MDSC accumulation in tumors and showed that hypoxic cancer cells secreted CCL26 to attract MDSCs33
Summary
Myeloid-derived suppressor cells (MDSCs) possess immunosuppressive activities, which allow cancers to escape immune surveillance and become non-responsive to immune checkpoints blockade. 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. We demonstrated in HCC model that hypoxic cancer cells recruit CX3CR1-expressing MDSCs to the tumor through chemokine (C–C motif) ligand 26 (CCL26)[17]. Extracellular ATP is hydrolyzed to 5′-AMP by ectonucleoside triphosphate diphosphohydrolase (ENTPD1, CD39), whereas extracellular 5′-AMP is further hydrolyzed to adenosine by 5′-nucleotidase (NT5E, CD73) These extracellular metabolites are known to tightly regulate neurotransmission and immune responses through interacting with the purigenic (G-coupled) receptors P2 and P1. ENTPD inhibitor, through suppressing ATP conversion to 5′-AMP, restores the recruitment of T and dendritic cells, and enhances the efficiency of chemotherapeutic agents in fibrosarcoma mouse model[21]
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