Antigen dominance hierarchies shape TCF1(+) progenitor CD8 T cell phenotypes in tumors.
Antigen dominance hierarchies shape TCF1(+) progenitor CD8 T cell phenotypes in tumors.
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DOI：
10.1016/j.cell.2021.08.020
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发表时间：
2021-09-16
期刊：
影响因子：
64.5
通讯作者：
Jacks T
中科院分区：
文献类型：
--
作者：
Burger ML;Cruz AM;Crossland GE;Gaglia G;Ritch CC;Blatt SE;Bhutkar A;Canner D;Kienka T;Tavana SZ;Barandiaran AL;Garmilla A;Schenkel JM;Hillman M;de Los Rios Kobara I;Li A;Jaeger AM;Hwang WL;Westcott PMK;Manos MP;Holovatska MM;Hodi FS;Regev A;Santagata S;Jacks T
CD8 T 细胞针对不同肿瘤新抗原的反应同时发生，但人们对反应之间的相互作用及其对 T 细胞功能和肿瘤控制的影响知之甚少。在小鼠肺腺癌中，我们发现肿瘤中建立了免疫优势，其中 CD8 T 细胞扩增主要由最稳定地结合 MHC 的抗原驱动。对次优势抗原做出反应的 T 细胞富集了与免疫检查点阻断 (ICB) 治疗反应相关的 TCF1+ 祖细胞表型。然而，由于以 CCR6 和 Tc17 分化为标志的 TCF1+ 细胞亚群功能失调，次优势 T 细胞反应并未优先受益于 ICB。对人类样本和测序数据集的分析表明，CCR6+ TCF1+ 细胞存在于人类癌症中，并且与 ICB 反应无关。疫苗接种消除了 CCR6+ TCF1+ 细胞并显着改善了次优势反应，突出了最佳地同时针对肿瘤产生新抗原反应的策略。对肺癌模型中抗原优势层次和动态的分析强调了优化 T 细胞针对次优势新抗原的反应的机会，以便通过调整 T 细胞祖细胞亚群的疫苗接种获得更好的检查点封锁反应
CD8 T cell responses against different tumor neoantigens occur simultaneously, yet little is known about the interplay between responses and its impact on T cell function and tumor control. In mouse lung adenocarcinoma, we found that immunodominance is established in tumors, wherein CD8 T cell expansion is predominantly driven by the antigen that most stably binds MHC. T cells responding to subdominant antigens were enriched for a TCF1+ progenitor phenotype correlated with response to immune checkpoint blockade (ICB) therapy. However, the subdominant T cell response did not preferentially benefit from ICB due to a dysfunctional subset of TCF1+ cells marked by CCR6 and Tc17 differentiation. Analysis of human samples and sequencing datasets revealed that CCR6+ TCF1+ cells exist across human cancers and are not correlated with ICB response. Vaccination eliminated CCR6+ TCF1+ cells and dramatically improved the subdominant response, highlighting a strategy to optimally engage concurrent neoantigen responses against tumors. Analysis of antigen dominance hierarchy and dynamics in a lung cancer model highlights the opportunity of optimizing T cell responses against subdominant neoantigens for better checkpoint blockade response through vaccination that adjusts T cell progenitor subpopulations
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影响因子：
46.9
作者：
Bolotin DA;Poslavsky S;Davydov AN;Frenkel FE;Fanchi L;Zolotareva OI;Hemmers S;Putintseva EV;Obraztsova AS;Shugay M;Ataullakhanov RI;Rudensky AY;Schumacher TN;Chudakov DM
通讯作者：
Chudakov DM
影响因子：
14.9
作者：
Baldarelli RM;Smith CM;Finger JH;Hayamizu TF;McCright IJ;Xu J;Shaw DR;Beal JS;Blodgett O;Campbell J;Corbani LE;Frost PJ;Giannatto SC;Miers DB;Kadin JA;Richardson JE;Ringwald M
通讯作者：
Ringwald M
影响因子：
64.8
作者：
Cao, Junyue;Spielmann, Malte;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
64.8
作者：
Harris CR;Millman KJ;van der Walt SJ;Gommers R;Virtanen P;Cournapeau D;Wieser E;Taylor J;Berg S;Smith NJ;Kern R;Picus M;Hoyer S;van Kerkwijk MH;Brett M;Haldane A;Del Río JF;Wiebe M;Peterson P;Gérard-Marchant P;Sheppard K;Reddy T;Weckesser W;Abbasi H;Gohlke C;Oliphant TE
通讯作者：
Oliphant TE
DOI：
10.1073/pnas.1201586109
发表时间：
2012-03-20
影响因子：
11.1
作者：
Eisen, Herman N.;Hou, Xun Helen;Cohen, Richard J.
通讯作者：
Cohen, Richard J.