Hypoxia induces myeloid‐derived suppressor cell recruitment to hepatocellular carcinoma through chemokine (C‐C motif) ligand 26

Abstract

A population of stromal cells, myeloid-derived suppressor cells (MDSCs), is present in tumors. Though studies have gradually revealed the protumorigenic functions of MDSCs, the molecular mechanisms guiding MDSC recruitment remain largely elusive. Hypoxia, O 2 deprivation, is an important factor in the tumor microenvironment of solid cancers, whose growth often exceeds the growth of functional blood vessels. Here, using hepatocellular carcinoma as the cancer model, we show that hypoxia is an important driver of MDSC recruitment. We observed that MDSCs preferentially infiltrate into hypoxic regions in human hepatocellular carcinoma tissues and that hypoxia-induced MDSC infiltration is dependent on hypoxia-inducible factors. We further found that hypoxia-inducible factors activate the transcription of chemokine (C-C motif) ligand 26 in cancer cells to recruit chemokine (C-X3-C motif) receptor 1-expressing MDSCs to the primary tumor. Knockdown of chemokine (C-C motif) ligand 26 in cancer cells profoundly reduces MDSC recruitment, angiogenesis, and tumor growth. Therapeutically, blockade of chemokine (C-C motif) ligand 26 production in cancer cells by the hypoxia-inducible factor inhibitor digoxin or blockade of chemokine (C-X3-C motif) receptor 1 in MDSCs by chemokine (C-X3-C motif) receptor 1 neutralizing antibody could substantially suppress MDSC recruitment and tumor growth. Conclusion: Cancer cells direct MDSC homing to primary tumor, suggesting that targeting MDSC recruitment represents an attractive therapeutic approach against solid cancers. (HEPATOLOGY 2016;64:797-813) H epatocellular carcinoma (HCC) is the fifth most common and the second most lethal malignancy in the world. Prognosis of HCC remains poor due to late symptom presentation and lack of efficient treatments. (1) The most promising curative HCC treatments are surgical resection and liver transplantation, which are feasible only for less than 30% of patients due to poor liver function or metastasis. (2) Sorafenib, the only Food and Drug Administrationapproved drug for HCC treatment, extends survival of patients for less than 3 months. (3) Thus, new HCC therapeutic strategies are much warranted.Myeloid-derived suppressor cells (MDSCs), a population of bone marrow-derived myeloid progenitors, are present in the tumors of patients and highly protumorigenic. (4)(5)(6) In humans, they are mainly Abbreviations: Ab, antibody; CA5/CA9, carbonic anhydrases V and IX; CCL26, chemokine (C-C motif) ligand

Ly6Clo monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy

“…Treatment with the negative control 7C1-siLUC (silencing luciferase mRNA) did not change tumor growth or immune cell infiltration, and there was Furthermore, we find that immunosuppression, rather than angiogenesis, in the tumor microenvironment is the key mechanism conferring resistance to anti-VEGF therapy exerted by Ly6C Some reports show that low doses of anti-VEGF therapy can induce vascular normalization and improve antitumor immunity (63,64). It is also known that high dose or prolonged treatment of anti-VEGF therapy promotes hypoxia and immunosuppression in the tumor microenvironment in both clinical and preclinical studies (1,6,24,(65)(66)(67)(68). The latter case explains one mechanism of anti-VEGF therapy resistance in patients, which is consistent with our observations in CRC models.…”

Neutrophil count is associated with myeloid derived suppressor cell level and presents prognostic value for hepatocellular carcinoma patients

“…Thus, neutrophils consisted of normal neutrophils and PMN-MDSCs. Elevation of PMN-MDSC had been confirmed in HCC patients by multiple studies [1–3]. The heterogeneity in PMN-MDSC levels among HCC patients decreased the accuracy of the patient selection for MDSCs targeted therapy.…”

The Role of Myeloid-Derived Suppressor Cells in Viral Infection

“…TGF-b also upregulated CXCR4 on MDSCs, resulting in increased recruitment to tumors, through micro-RNA-494 (6,91,168). Similarly, hypoxia was shown to increase CCL26 expression on cancer cells, leading to recruitment of CX 3 CR1-expressing MDSCs (22).…”