한빛사 논문
Jun-Kyu Byun1,2,8, Mihyang Park3,8, Seunghyeong Lee3, Jae Won Yun4,5, Jaebon Lee6, Jae Sun Kim6, Sung Jin Cho7, Hui-Jeon Jeon7, In-Kyu Lee1,2,3, Yeon-Kyung Choi1,2,*, Keun-Gyu Park1,2,3,9,*
1Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, South Korea
2Research Institute of Aging and Metabolism, Kyungpook National University, Daegu 41566, South Korea
3Department of Biomedical Science, Graduate School, Kyungpook National University, Daegu 41566, South Korea
4Veterans Medical Research Institute, Veterans Health Service Medical Center, Seoul 05368, South Korea
5Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06355, South Korea
6Sungkyunkwan University School of Medicine, Seoul 16419, South Korea
7New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, South Korea
8These authors contributed equally
9Lead Contact
*Corresponding author
Abstract
Despite its outstanding clinical success, immune checkpoint blockade remains ineffective in many patients. Accordingly, combination therapy capable of achieving greater antitumor immunity is urgently required. Here, we report that limiting glutamine metabolism in cancer cells bolsters the effectiveness of anti-programmed death ligand-1 (PD-L1) antibody. Inhibition of glutamine utilization increased PD-L1 levels in cancer cells, thereby inactivating co-cultured T cells. Under glutamine-limited conditions, reduced cellular GSH levels caused an upregulation of PD-L1 expression by impairing SERCA activity, which activates the calcium/NF-κB signaling cascade. Consequently, in tumors grown in immunocompetent mice, inhibition of glutamine metabolism decreased the antitumor activity of T cells. In combination with anti-PD-L1, however, glutamine depletion strongly promoted the antitumor efficacy of T cells in vitro and in vivo due to simultaneous increases in Fas/CD95 levels. Our results demonstrate the relevance of cancer glutamine metabolism to antitumor immunity and suggest that co-targeting of glutamine metabolism and PD-L1 represents a promising therapeutic approach.
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TOP52020년 후보
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