Anti-PD-L1/TGF-BR fusion protein (SHR-1701) overcomes disrupted lymphocyte recovery-induced resistance to PD-1/PD-L1 inhibitors in lung cancer  

作　　者：Bo Cheng Kaikai Ding Pengxiang Chen Jianxiong Ji Tao Luo Xiaofan Guo Wei Qiu Chunhong Ma Xue Meng Jian Wang Jinming Yu Yuan Liu 

机构地区：[1]Department of Radiation Oncology,Shandong Cancer Hospital and Institute,Cheeloo College of Medicine,Shandong University,Jinan,Shandong 250012,P.R.China [2]Department of Radiation Oncology,Qilu Hospital of Shandong University,Cheeloo College of Medicine,Shandong University,Jinan,Shandong 250012,P.R.China [3]Department of Neurosurgery,Qilu Hospital of Shandong University,Cheeloo College of Medicine,Shandong University,Jinan,Shandong 250012,P.R.China [4]Department of Neurology,Loma Linda University Health,Loma Linda,CA 92354,USA [5]Shandong Key Laboratory of Brain Functional Remodeling,Jinan,Shandong 250012,P.R.China [6]Department of Biomedicine,University of Bergen,Bergen 5009,Norway [7]Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology,Shandong University School of Medicine,Jinan,Shandong 250012,P.R.China [8]Department of Neurosurgery,the Second Affiliated Hospital of Zhejiang University School of Medicine,Hangzhou,Zhejiang 310000,P.R.China

出　　处：《Cancer Communications》2022年第1期17-36,共20页癌症通讯（英文）

基　　金：NationalKeyResearch and Develop-ment Projects of China,Grant/Award Number:2018YFC1312201;Academic Promotion Programof Shandong First Medical University,Grant/AwardNum-ber:2019ZL002;NationalNatural Sci-ence Foundation of China,Grant/Award Numbers:81803096,81972863,81627901,82030082;Natural Science Foundation of Shandong Province,Grant/AwardNum-ber:ZR201807080057;Cancer Institute and Hospital,ChineseAcademy of Medical Sci-ences,Grant/Award Number:2019RU071;supported by funding from the Shandong Provincial Natural Science Foundation(ZR201807080057),the National Key Research and Development Projects of China(2018YFC1312201),Cancer Institute and Hospital,Chinese Academy of Medical Sciences(2019RU071),the Academic Promotion Program of Shandong First Medical University(2019ZL002),and the National Natural Science Foundation of China(81803096,81972863,81627901,and 82030082).

摘　　要：Background:Second-generation programmed cell death-protein 1/pro-grammed death-ligand 1(PD-1/PD-L1)inhibitors,such as bintrafusp alfa(M7824),SHR-1701,and YM101,have been developed to simultaneously block PD-1/PD-L1 and transforming growth factor-beta/transforming growth factor-beta receptor(TGF-P/TGF-βR).Consequently,it is necessary to identify predictive factors of lung cancer patients who are not only resistant to PD-1/PD-LI inhibitors but also sensitive to bifunctional drugs.The purpose of this study was to search for such predictors.Methods:Multivariable Cox regression was used to study the association between the clinical outcome of treatment with PD-1/PD-L1 inhibitors and lym-phocyte recovery after lymphopenia in lung cancer patients.Murine CMT167 lung cancer cells were engineered to express the firefly luciferase gene and implanted orthotopically in the lung of syngeneic mice.Bioluminescence imag-ing,flow cytometry,and immunohistochemistry were employed to detrmine response to immunotherapy and function of tumor-infiltrating immune cells.Results:For lung cancer patients treated with anti-PD-1/PD-LI antibodies,poor lymphocyte recovery was associated with a shorter progression-free survival(PFS;P<0.001),an accumulation of regulatory T cells(Tregs),and an elimi-nation of CD8+T cells in the peripheral blood.Levels of CD8+T cells and Treg cells were also imbalanced in the tumors and peripheral immune organs of mice with poor lymphocyte recovery after chemotherapy.Moreover,these mice failed to respond to anti-PD-1 antibodies but remained sensitive to the anti-PD-LI/TGF-βR fusion protein(SHR-1701).Consistently,SHR-1701 but not anti-PD-1 antibod-ies,markedly enhanced IFN-γproduction and Ki-67 expression in peripheral CD8+T cells from patients with impaired lymphocyte recovery.Conclusions:Lung cancer patients with poor lymphocyte recovery and suffer-ing from persistent lymphopenia after previous chemotherapy are resistant to anti-PD-1/PD-L1 antibodies but might be sensitive to second-generation agents such as SH

关 键 词：SHR IMPAIRED markedly 

分 类 号：R73[医药卫生—肿瘤]