4-1BB(CD137)is a strong enhancer of the proliferation of CD8^(+)T cells.Since these cells require increased production of energy and biomass to support their proliferation,we hypothesized that 4-1BB signaling activate...4-1BB(CD137)is a strong enhancer of the proliferation of CD8^(+)T cells.Since these cells require increased production of energy and biomass to support their proliferation,we hypothesized that 4-1BB signaling activated glucose and fatty acid metabolism.We found that treatment with agonistic anti-4-1BB mAb promoted the proliferation of CD8^(+)T cells in vitro,increasing their size and granularity.Studies with a glycolysis inhibitor and a fatty acid oxidation inhibitor revealed that CD8^(+)T cell proliferation required both glucose and fatty acid metabolism.Anti-4-1BB treatment increased glucose transporter 1 expression and activated the liver kinase B1(LKB1)-AMP-activated protein kinase(AMPK)-acetyl-CoA carboxylase(ACC)signaling pathway,which may be responsible for activating the metabolism of glucose and fatty acids.We also examined whether blocking glucose or fatty acid metabolism affected cell cycle progression and the anti-apoptotic effect of 4-1BB signaling.The increase of anti-apoptotic factors and cyclins in response to anti-4-1BB treatment was completely prevented by treating CD8^(+)T cells with the fatty acid oxidation inhibitor,etomoxir,but not with the glycolysis inhibitor,2-deoxy-D-glucose.We conclude that anti-4-1BB treatment activates glucose and fatty acid metabolism thus supporting the increased demand for energy and biomass,and that fatty acid metabolism plays a crucial role in enhancing the cell cycle progression of anti-CD3-activated CD8^(+)T cells in vitro and the anti-apoptotic effects of 4-1BB signaling on these cells.展开更多
卵巢上皮性癌（卵巢癌）的治疗方法包括手术结合化疗或放疗，但以上方法均未能使晚期卵巢癌患者约30％的5年生存率得以改善，使卵巢癌成为妇科肿瘤中的治疗难点，促使我们寻找新的治疗手段。近年来，免疫治疗成为肿瘤治疗的新辅助方法...卵巢上皮性癌（卵巢癌）的治疗方法包括手术结合化疗或放疗，但以上方法均未能使晚期卵巢癌患者约30％的5年生存率得以改善，使卵巢癌成为妇科肿瘤中的治疗难点，促使我们寻找新的治疗手段。近年来，免疫治疗成为肿瘤治疗的新辅助方法，显示了一定的治疗效果，其中CD4^＋CD25^＋去调节性T淋巴细胞（regulatory T cells，Tr细胞）成为研究热点，并逐渐从基础研究过渡到临床研究，本文就其在卵巢癌中的研究进展进行综述。展开更多
基金funded by grants from the National Cancer Center of Korea(NCC-1310430)the National Research Foundation of Korea(NRF-2005-0093837,NRF-2013R1A1A2008703)+1 种基金the Korea Drug Development Fund(KDDF-201408-11)the Ministry of Trade,Industry and Energy of Korea(GLOBAL R&D PROJECT,N0000901).
文摘4-1BB(CD137)is a strong enhancer of the proliferation of CD8^(+)T cells.Since these cells require increased production of energy and biomass to support their proliferation,we hypothesized that 4-1BB signaling activated glucose and fatty acid metabolism.We found that treatment with agonistic anti-4-1BB mAb promoted the proliferation of CD8^(+)T cells in vitro,increasing their size and granularity.Studies with a glycolysis inhibitor and a fatty acid oxidation inhibitor revealed that CD8^(+)T cell proliferation required both glucose and fatty acid metabolism.Anti-4-1BB treatment increased glucose transporter 1 expression and activated the liver kinase B1(LKB1)-AMP-activated protein kinase(AMPK)-acetyl-CoA carboxylase(ACC)signaling pathway,which may be responsible for activating the metabolism of glucose and fatty acids.We also examined whether blocking glucose or fatty acid metabolism affected cell cycle progression and the anti-apoptotic effect of 4-1BB signaling.The increase of anti-apoptotic factors and cyclins in response to anti-4-1BB treatment was completely prevented by treating CD8^(+)T cells with the fatty acid oxidation inhibitor,etomoxir,but not with the glycolysis inhibitor,2-deoxy-D-glucose.We conclude that anti-4-1BB treatment activates glucose and fatty acid metabolism thus supporting the increased demand for energy and biomass,and that fatty acid metabolism plays a crucial role in enhancing the cell cycle progression of anti-CD3-activated CD8^(+)T cells in vitro and the anti-apoptotic effects of 4-1BB signaling on these cells.
文摘卵巢上皮性癌（卵巢癌）的治疗方法包括手术结合化疗或放疗，但以上方法均未能使晚期卵巢癌患者约30％的5年生存率得以改善，使卵巢癌成为妇科肿瘤中的治疗难点，促使我们寻找新的治疗手段。近年来，免疫治疗成为肿瘤治疗的新辅助方法，显示了一定的治疗效果，其中CD4^＋CD25^＋去调节性T淋巴细胞（regulatory T cells，Tr细胞）成为研究热点，并逐渐从基础研究过渡到临床研究，本文就其在卵巢癌中的研究进展进行综述。
