Enforced PGC-1α expression promotes CD8 T cell fitness, memory formation and antitumor immunity.
Enforced PGC-1α expression promotes CD8 T cell fitness, memory formation and antitumor immunity.
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DOI：
10.1038/s41423-020-0365-3
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发表时间：
2021-07
影响因子：
24.1
通讯作者：
Zhang L
中科院分区：
文献类型：
--
作者：
Dumauthioz N;Tschumi B;Wenes M;Marti B;Wang H;Franco F;Li W;Lopez-Mejia IC;Fajas L;Ho PC;Donda A;Romero P;Zhang L
记忆CD 8 T细胞可以提供长期的抗肿瘤保护，这取决于它们增强的增殖能力，自我更新和独特的代谢重新布线以维持细胞健康。具体而言，记忆CD 8 T细胞参与氧化磷酸化和脂肪酸氧化以满足其代谢需求。相反，肿瘤浸润淋巴细胞（TIL）显示严重的代谢缺陷，这可能是其功能下降的基础。在这里，我们表明，增殖物激活受体γ辅激活因子1-α（PGC-1α），线粒体生物发生（MB）的主调节因子的过度表达，有利于CD 8 T细胞的中央记忆的形成，而不是常驻记忆的产生。PGC-1α过表达的CD 8 T细胞持续存在，并介导对细菌感染或肽疫苗接种的更强的回忆反应。重要的是，具有增强的PGC-1α表达的CD 8 T细胞在小鼠黑素瘤模型中提供更强的抗肿瘤免疫力。此外，当在无肿瘤宿主中再激发时，过表达PGC-1α的TIL保持较高的线粒体活性和改善的扩增。总之，我们的研究结果表明，加强线粒体生物合成促进体内CD 8 T细胞记忆形成，代谢适应性和抗肿瘤免疫。
Memory CD8 T cells can provide long-term protection against tumors, which depends on their enhanced proliferative capacity, self-renewal and unique metabolic rewiring to sustain cellular fitness. Specifically, memory CD8 T cells engage oxidative phosphorylation and fatty acid oxidation to fulfill their metabolic demands. In contrast, tumor-infiltrating lymphocytes (TILs) display severe metabolic defects, which may underlie their functional decline. Here, we show that overexpression of proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), the master regulator of mitochondrial biogenesis (MB), favors CD8 T cell central memory formation rather than resident memory generation. PGC-1α-overexpressing CD8 T cells persist and mediate more robust recall responses to bacterial infection or peptide vaccination. Importantly, CD8 T cells with enhanced PGC-1α expression provide stronger antitumor immunity in a mouse melanoma model. Moreover, TILs overexpressing PGC-1α maintain higher mitochondrial activity and improved expansion when rechallenged in a tumor-free host. Altogether, our findings indicate that enforcing mitochondrial biogenesis promotes CD8 T cell memory formation, metabolic fitness, and antitumor immunity in vivo.
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影响因子：
30.5
作者：
Chang CH;Pearce EL
通讯作者：
Pearce EL
影响因子：
29
作者：
Sukumar M;Liu J;Mehta GU;Patel SJ;Roychoudhuri R;Crompton JG;Klebanoff CA;Ji Y;Li P;Yu Z;Whitehill GD;Clever D;Eil RL;Palmer DC;Mitra S;Rao M;Keyvanfar K;Schrump DS;Wang E;Marincola FM;Gattinoni L;Leonard WJ;Muranski P;Finkel T;Restifo NP
通讯作者：
Restifo NP
影响因子：
15.9
作者：
Sukumar, Madhusudhanan;Liu, Jie;Gattinoni, Luca
通讯作者：
Gattinoni, Luca
影响因子：
30.5
作者：
Kaech, SM;Tan, JT;Ahmed, R
通讯作者：
Ahmed, R
影响因子：
64.5
作者：
Ho PC;Bihuniak JD;Macintyre AN;Staron M;Liu X;Amezquita R;Tsui YC;Cui G;Micevic G;Perales JC;Kleinstein SH;Abel ED;Insogna KL;Feske S;Locasale JW;Bosenberg MW;Rathmell JC;Kaech SM
通讯作者：
Kaech SM