Chemical augmentation of mitochondrial electron transport chains tunes T cell activation threshold in tumors.
Chemical augmentation of mitochondrial electron transport chains tunes T cell activation threshold in tumors.
复制标题
DOI：
10.1136/jitc-2021-003958
复制
发表时间：
2022-03
影响因子：
10.9
通讯作者：
Ikeda H
中科院分区：
文献类型：
--
作者：
Dotsu Y;Muraoka D;Ogo N;Sonoda Y;Yasui K;Yamaguchi H;Yagita H;Mukae H;Asai A;Ikeda H
癌症免疫疗法对低免疫原性肿瘤显示出不足的功效。此外，肿瘤通常下调抗原和主要组织相容性复合物表达以逃避T细胞的识别，导致肿瘤微环境中T细胞受体（TCR）刺激不足。因此，增强TCR介导的肿瘤抗原识别是提高癌症免疫治疗功效的有用策略。我们从我们的文库中筛选了310种小分子，并鉴定了PQDN，这是一种在TCR接合后激活CD 8 T细胞的小分子，即使抗原刺激太弱而无法激活。我们使用线粒体功能抑制剂和Seahorse通量分析仪来研究PQDN对T细胞作用的机制。使用流式细胞术和TCR库分析检测PQDN对肿瘤浸润性CD 8 T细胞的作用。PQDN通过增强电子传递链（ETC）增加线粒体的相互作用能力，并通过mTOR/AKT信号转导促进糖酵解，导致CD 8 T细胞活化增强，即使抗原刺激非常弱。将该化合物瘤内给药至荷瘤小鼠中可调节具有肿瘤抗原识别能力的灭活T细胞，并扩大肿瘤浸润T细胞的功能性T细胞受体多样性，增强抗肿瘤免疫应答并延缓肿瘤生长。此外，即使在低免疫原性肿瘤中，PQDN也具有与T细胞依赖性免疫疗法如检查点抑制疗法或过继细胞疗法的协同效力。我们还证明了该化合物增强了人CD 8 T细胞的活化。这些数据表明，通过线粒体ETC的化学活化来调节T细胞活化阈值是通过活化低亲合力肿瘤特异性T细胞来改善治疗功效的新策略。
Cancer immunotherapy shows insufficient efficacy for low immunogenic tumors. Furthermore, tumors often downregulate antigen and major histocompatibility complex expression to escape recognition by T cells, resulting in insufficient T cell receptor (TCR) stimulation in the tumor microenvironment. Thus, augmenting TCR-mediated recognition of tumor antigens is a useful strategy to improve the efficacy of cancer immunotherapy. We screened 310 small molecules from our library and identified PQDN, a small molecule that activates CD8 T cells after TCR engagement, even when antigen stimulation is too weak for their activation. We used inhibitors of mitochondrial functions and Seahorse Flux Analyzer to investigate the mechanism underlying the effect of PQDN on T cells. Effect of PQDN on tumor-infiltrating CD8 T cells was examined using flow cytometry and TCR repertoire analysis. PQDN increased mitochondrial reciprocal capacity through enhancement of electron transport chains (ETCs) and facilitated glycolysis via mTOR/AKT signaling, resulting in augmented CD8 T cell activation, even when antigen stimulation is extremely weak. Intratumoral administration of this compound into tumor-bearing mice tunes inactivated T cell with tumor antigen recognition potent and expanded functional T cell receptor diversity of tumor-infiltrating T cells, augmenting antitumor immune responses and retarding tumor growth. Furthermore, PQDN has a synergistic potent with T cell dependent immunotherapy, such as checkpoint inhibitory therapy or adoptive cell therapy, even in a low immunogenic tumor. We also demonstrated that this compound enhances the activation of human CD8 T cells. These data suggest that tuning the T cell activation threshold by chemical activation of mitochondrial ETC is a new strategy for improving therapeutic efficacy through the activation of low-avidity tumor-specific T cells.
登录
查看更多内容
影响因子：
30.5
作者：
Guo Y;Xie YQ;Gao M;Zhao Y;Franco F;Wenes M;Siddiqui I;Bevilacqua A;Wang H;Yang H;Feng B;Xie X;Sabatel CM;Tschumi B;Chaiboonchoe A;Wang Y;Li W;Xiao W;Held W;Romero P;Ho PC;Tang L
通讯作者：
Tang L
影响因子：
16.6
作者：
Klein-Hessling S;Muhammad K;Klein M;Pusch T;Rudolf R;Flöter J;Qureischi M;Beilhack A;Vaeth M;Kummerow C;Backes C;Schoppmeyer R;Hahn U;Hoth M;Bopp T;Berberich-Siebelt F;Patra A;Avots A;Müller N;Schulze A;Serfling E
通讯作者：
Serfling E
影响因子：
32.4
作者：
Levine LS;Hiam-Galvez KJ;Marquez DM;Tenvooren I;Madden MZ;Contreras DC;Dahunsi DO;Irish JM;Oluwole OO;Rathmell JC;Spitzer MH
通讯作者：
Spitzer MH
影响因子：
64.5
作者：
Chang CH;Curtis JD;Maggi LB Jr;Faubert B;Villarino AV;O'Sullivan D;Huang SC;van der Windt GJ;Blagih J;Qiu J;Weber JD;Pearce EJ;Jones RG;Pearce EL
通讯作者：
Pearce EL
DOI：
10.1073/pnas.1620433114
发表时间：
2017-01-31
影响因子：
11.1
作者：
Chamoto, Kenji;Chowdhury, Partha S.;Honjo, Tasuku
通讯作者：
Honjo, Tasuku