Chronic activation of 4-1BB signaling induces granuloma development in tumor-draining lymph nodes that is detrimental to subsequent CD8^(+)T cell responses  

作　　者：Seon-Hee Kim Rohit Singh Chungyong Han Eunjung Cho Yu I.Kim Don G.Lee Young H.Kim Sang Soo Kim Dong Hoon Shin Hye Jin You Hyeon-Woo Lee Byoung S.Kwon Beom K.Choi 

机构地区：[1]Division of Tumor Immunology,National Cancer Center,Goyang,10408,Republic of Korea [2]Graduate School of Cancer Science and Policy,National Cancer Center,Goyang,10408,Republic of Korea [3]Biomedicine Production Branch,Program for Immunotherapy Research,Goyang,10408,Republic of Korea [4]Eutilex Institute for Biomedical Research,Eutilex,Co.,Ltd.,Seoul,08594,Republic of Korea [5]Division of Convergence Technology,National Cancer Center,Goyang,10408,Republic of Korea [6]Division of Translational Science,National Cancer Center,Goyang,10408,Republic of Korea [7]Institute of Oral Biology,School of Dentistry,Graduate School,Kyung Hee University,Seoul,02447,Republic of Korea [8]Department of Medicine,Tulane University Health Sciences Center,New Orleans,LA,70112,USA

出　　处：《Cellular & Molecular Immunology》2021年第8期1956-1968,共13页中国免疫学杂志（英文版）

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]).

摘　　要：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.

关 键 词：4-1BB COSTIMULATION GRANULOMA CD8 lymphocyte MACROPHAGE 

分 类 号：R392[医药卫生—免疫学]