Yuan Fang1, Weiren Liu1, Zheng Tang1, Xiang Ji2, Yufu Zhou1,3, Shushu Song1,4, Mengxin Tian1,5, Chenyang Tao1, Run Huang1, Guiqi Zhu1, Xifei Jiang1, Jun Gao1, Weifeng Qu1, Han Wang1, Peiyun Zhou1, Xiaoling Wu1, Lei Jin1, Haixiang Sun1, Zhenbin Ding1, Yuanfei Peng1, Shimin Zhao6, Jian Zhou1, Jia Fan1, Wei Xu7, Yinghong Shi1. 1. Department of Liver Surgery, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China. 2. Department of Biochemistry, School of Life Sciences, Fudan University, Shanghai, P.R. China. 3. Department of Immunology and Pathogenic Biology, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, P. R. China. 4. Department of Biochemistry and Molecular, School of Basic Medical Sciences, Fudan University, Shanghai, P.R. China. 5. Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P.R. China. 6. Institute of Metabolism and Integrative Biology, Obstetrics &, Gynecology Hospital of Fudan University, Shanghai, P.R. China. 7. Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Shanghai Fifth People's Hospital, Fudan University, Shanghai, P.R. China.
Abstract
BACKGROUND AND AIMS: Monocarboxylate transporter (MCT) 4 is a high-affinity lactate transporter that is primarily involved in the maintenance of intracellular pH homeostasis and highly expressed in different tumors. However, the role of MCT4 in modulating immune responses against HCC remains unknown. APPROACH AND RESULTS: In this study, we demonstrated that MCT4 was overexpressed in HCC, which was associated with poor prognosis in patients. Genetic or pharmacological inhibition of MCT4 using VB124 (a highly potent MCT4 inhibitor) suppressed HCC tumor growth in immunocompetent mice model by enhancing CD8+ T cell infiltration and cytotoxicity. Such improved immunotherapy response by MCT4 targeting was due to combined consequences characterized by the alleviated acidification of tumor microenvironment and elevated the chemokine (C-X-C motif) ligand (CXCL) 9/CXCL10 secretion induced by reactive oxygen species/NF-κB signaling pathway. Combining MCT4 inhibition improved the therapeutic benefit of anti-programmed cell death 1 immunotherapy in HCC and prolonged mice survival. Moreover, higher MCT4 expression was observed in tumor tissues from nonresponder patients with HCC receiving neoadjuvant therapy with toripalimab. CONCLUSIONS: Our results revealed that lactate exportation by MCT4 has a tumor-intrinsic function in generating an immunosuppressive HCC environment and demonstrated the proof of the concept of targeting MCT4 in tailoring HCC immunotherapeutic approaches.
BACKGROUND AND AIMS: Monocarboxylate transporter (MCT) 4 is a high-affinity lactate transporter that is primarily involved in the maintenance of intracellular pH homeostasis and highly expressed in different tumors. However, the role of MCT4 in modulating immune responses against HCC remains unknown. APPROACH AND RESULTS: In this study, we demonstrated that MCT4 was overexpressed in HCC, which was associated with poor prognosis in patients. Genetic or pharmacological inhibition of MCT4 using VB124 (a highly potent MCT4 inhibitor) suppressed HCC tumor growth in immunocompetent mice model by enhancing CD8+ T cell infiltration and cytotoxicity. Such improved immunotherapy response by MCT4 targeting was due to combined consequences characterized by the alleviated acidification of tumor microenvironment and elevated the chemokine (C-X-C motif) ligand (CXCL) 9/CXCL10 secretion induced by reactive oxygen species/NF-κB signaling pathway. Combining MCT4 inhibition improved the therapeutic benefit of anti-programmed cell death 1 immunotherapy in HCC and prolonged mice survival. Moreover, higher MCT4 expression was observed in tumor tissues from nonresponder patients with HCC receiving neoadjuvant therapy with toripalimab. CONCLUSIONS: Our results revealed that lactate exportation by MCT4 has a tumor-intrinsic function in generating an immunosuppressive HCC environment and demonstrated the proof of the concept of targeting MCT4 in tailoring HCC immunotherapeutic approaches.