CXCR4 inhibition in tumor microenvironment facilitates anti‐programmed death receptor‐1 immunotherapy in sorafenib‐treated hepatocellular carcinoma in mice

索拉非尼 肿瘤微环境 癌症研究 免疫疗法 间质细胞 细胞毒性T细胞 医学 CD8型 肝细胞癌 免疫系统 免疫学 生物 生物化学 肿瘤细胞 体外
作者
Yunching Chen,Rakesh R. Ramjiawan,Thomas Reiberger,Mei Rosa Ng,Tai Hato,Yuhui Huang,Hiroki Ochiai,Shuji Kitahara,Elizabeth C. Unan,T. P. Reddy,Christopher Fan,Peigen Huang,Nabeel Bardeesy,Andrew X. Zhu,Rakesh K. Jain,Dan G. Duda
出处
期刊:Hepatology [Wiley]
卷期号:61 (5): 1591-1602 被引量:381
标识
DOI:10.1002/hep.27665
摘要

Sorafenib, a broad tyrosine kinase inhibitor, is the only approved systemic therapy for advanced hepatocellular carcinoma (HCC) but provides limited survival benefits. Recently, immunotherapy has emerged as a promising treatment strategy, but its role remains unclear in HCCs, which are associated with decreased cytotoxic CD8 + T‐lymphocyte infiltration in both murine and human tumors. Moreover, in mouse models after sorafenib treatment intratumoral hypoxia is increased and may fuel evasive resistance. Using orthotopic HCC models, we now show that increased hypoxia after sorafenib treatment promotes immunosuppression, characterized by increased intratumoral expression of the immune checkpoint inhibitor programmed death ligand‐1 and accumulation of T‐regulatory cells and M2‐type macrophages. We also show that the recruitment of immunosuppressive cells is mediated in part by hypoxia‐induced up‐regulation of stromal cell–derived 1 alpha. Inhibition of the stromal cell–derived 1 alpha receptor (C‐X‐C receptor type 4 or CXCR4) using AMD3100 prevented the polarization toward an immunosuppressive microenvironment after sorafenib treatment, inhibited tumor growth, reduced lung metastasis, and improved survival. However, the combination of AMD3100 and sorafenib did not significantly change cytotoxic CD8 + T‐lymphocyte infiltration into HCC tumors and did not modify their activation status. In separate experiments, antibody blockade of the programmed death ligand‐1 receptor programmed death receptor‐1 (PD‐1) showed antitumor effects in treatment‐naive tumors in orthotopic (grafted and genetically engineered) models of HCC. However, anti‐PD‐1 antibody treatment had additional antitumor activity only when combined with sorafenib and AMD3100 and not when combined with sorafenib alone. Conclusion : Anti‐PD‐1 treatment can boost antitumor immune responses in HCC models; when used in combination with sorafenib, anti‐PD‐1 immunotherapy shows efficacy only with concomitant targeting of the hypoxic and immunosuppressive microenvironment with agents such as CXCR4 inhibitors. (H epatology 2015;61:1591–1602)
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