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
The antitumor capabilities of agonistic anti-4-1BB mAbs have made them an attractive target for tumor immunotherapy.However,the adverse side effects associated with agonist antibodies have hindered their clinical deve...The antitumor capabilities of agonistic anti-4-1BB mAbs have made them an attractive target for tumor immunotherapy.However,the adverse side effects associated with agonist antibodies have hindered their clinical development.Here,we aimed to study the immune-related adverse events of repeated doses and long-term use of agonistic anti-4-1BB mAbs.We show that chronic activation of 4-1BB signals induced the accumulation of IFN-γ-producing PD-1^(+)CD8^(+)T cells in the secondary lymphoid organs of tumor-bearing mice by increasing the number of dividing CD8^(+)T cells,which was beneficial for suppressing tumor growth in the early phase of anti-4-1BB induction.However,repeated exposure to anti-4-1BB mAbs led to granuloma development in tumor-draining lymph nodes(TDLNs)of mice due to recruitment and accumulation of macrophages via the CD8^(+)T cell-IFN-γaxis.This was accompanied by excessive lymph node swelling,which impaired the sequential activation of CD8^(+)T cells.Our data provide insights into the immune-related adverse events of long-term agonist 4-1BB antibody dosing,which should be considered during the clinical development of immunomodulating therapy.展开更多
4-1BB is an inducible receptor expressed on activated T cells,while its ligand,4-1BBL,is mainly expressed in antigen-presenting cells and macrophages[1,2].To the best of our knowledge,ligandmediated transactivation of...4-1BB is an inducible receptor expressed on activated T cells,while its ligand,4-1BBL,is mainly expressed in antigen-presenting cells and macrophages[1,2].To the best of our knowledge,ligandmediated transactivation of 4-1BB is responsible for the survival and immune effector functions of T cells.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.
基金This study was supported by the National Research Foundation of Korea(NRF)grant funded by the Korean government(2018R1A6A3A01011692[SHK]from MOE and 2019R1C1C1008999[CH]from MSIT)the National Cancer Center of Korea(NCC-1810102/191050/1911261[BKC]and NCC-2010190[CH]).
文摘The antitumor capabilities of agonistic anti-4-1BB mAbs have made them an attractive target for tumor immunotherapy.However,the adverse side effects associated with agonist antibodies have hindered their clinical development.Here,we aimed to study the immune-related adverse events of repeated doses and long-term use of agonistic anti-4-1BB mAbs.We show that chronic activation of 4-1BB signals induced the accumulation of IFN-γ-producing PD-1^(+)CD8^(+)T cells in the secondary lymphoid organs of tumor-bearing mice by increasing the number of dividing CD8^(+)T cells,which was beneficial for suppressing tumor growth in the early phase of anti-4-1BB induction.However,repeated exposure to anti-4-1BB mAbs led to granuloma development in tumor-draining lymph nodes(TDLNs)of mice due to recruitment and accumulation of macrophages via the CD8^(+)T cell-IFN-γaxis.This was accompanied by excessive lymph node swelling,which impaired the sequential activation of CD8^(+)T cells.Our data provide insights into the immune-related adverse events of long-term agonist 4-1BB antibody dosing,which should be considered during the clinical development of immunomodulating therapy.
基金This study was supported by the National Research Foundation of Korea(NRF)grant funded by the Korean government(2022R1A2C1005463[BKC],2022R1C1C1010078[SHK],and 2022R1C1C1003152[CH]from MSIT)by the National Cancer Center of Korea(NCC)grant funded by the Ministry of Health and Welfare(NCC-2212450[CH]).
文摘4-1BB is an inducible receptor expressed on activated T cells,while its ligand,4-1BBL,is mainly expressed in antigen-presenting cells and macrophages[1,2].To the best of our knowledge,ligandmediated transactivation of 4-1BB is responsible for the survival and immune effector functions of T cells.