Combination PD-1 and PD-L1 Blockade Promotes Durable Neoantigen-Specific T Cell-Mediated Immunity in Pancreatic Ductal Adenocarcinoma.
Combination PD-1 and PD-L1 Blockade Promotes Durable Neoantigen-Specific T Cell-Mediated Immunity in Pancreatic Ductal Adenocarcinoma.
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DOI：
10.1016/j.celrep.2019.07.059
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发表时间：
2019-08-20
期刊：
影响因子：
8.8
通讯作者：
Stromnes IM
中科院分区：
文献类型：
--
作者：
Burrack AL;Spartz EJ;Raynor JF;Wang I;Olson M;Stromnes IM
胰腺导管腺癌（PDA）是一种对免疫治疗有抵抗力的致命性癌症。我们创建了PDA小鼠模型，并表明肿瘤内T细胞积累和对免疫检查点阻断的反应需要新抗原表达。通过产生肽：MHC四聚体，我们确定PDA诱导快速的肿瘤内，和渐进的全身性，肿瘤特异性T细胞耗竭。单药PD-1或PD-L1阻断可增强全身性T细胞扩增，并诱导需要全身性T细胞的客观应答。然而，最终出现了IFNγ诱导的Tap 1和MHC I类细胞表面表达缺陷的肿瘤逃逸变体。PD-1 + PD-L1联合阻断通过增加瘤内KLRG 1 + Lag 3 −TNFα+肿瘤特异性T细胞并产生能够扩增至自发性肿瘤复发的记忆T细胞，从而延长动物生存期，在治疗上具有协同作用。我们的研究支持PD-1和PD-L1是PDA中相关的免疫检查点，并确定了在具有新抗原特异性T细胞的患者中进行临床测试的组合。Burrack等人研究了胰腺癌免疫治疗期间的肿瘤特异性T细胞。T细胞在肿瘤内积聚，但很快耗尽。联合PD-1 + PD-L1阻断可促进外周T细胞扩增、TNFα产生，并在50%的动物中根除自发性肿瘤复发。最终出现IFNγ诱导型Tap 1和MHC I类缺陷的肿瘤变体。
Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer resistant to immunotherapy. We create a PDA mouse model and show that neoantigen expression is required for intratumoral T cell accumulation and response to immune checkpoint blockade. By generating a peptide:MHC tetramer, we identify that PDA induces rapid intratumoral, and progressive systemic, tumor-specific T cell exhaustion. Monotherapy PD-1 or PD-L1 blockade enhances systemic T cell expansion and induces objective responses that require systemic T cells. However, tumor escape variants defective in IFNγ-inducible Tap1 and MHC class I cell surface expression ultimately emerge. Combination PD-1 + PD-L1 blockade synergizes therapeutically by increasing intratumoral KLRG1+Lag3−TNFα+ tumor-specific T cells and generating memory T cells capable of expanding to spontaneous tumor recurrence, thereby prolonging animal survival. Our studies support that PD-1 and PD-L1 are relevant immune checkpoints in PDA and identify a combination for clinical testing in those patients with neoantigen-specific T cells. Burrack et al. investigate tumor-specific T cells during immunotherapy of pancreas cancer. T cells accumulate intratumorally yet rapidly exhaust. Combined PD-1 + PD-L1 blockade promotes peripheral T cell expansion, TNFα production, and eradication of spontaneous tumor recurrence in 50% of animals. Tumor variants defective in IFNγ-inducible Tap1 and MHC class I ultimately emerge.
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影响因子：
11.2
作者：
Donia, Marco;Harbst, Katja;Svane, Inge Marie
通讯作者：
Svane, Inge Marie
非小细胞肺癌转移中KRAS基因突变与HLA I类抗原下调的关系
影响因子：
1.6
作者：
He, Xiao-Peng;Song, Fu-Jie;Jiang, Wen-Peng
通讯作者：
Jiang, Wen-Peng
影响因子：
82.9
作者：
Gros A;Parkhurst MR;Tran E;Pasetto A;Robbins PF;Ilyas S;Prickett TD;Gartner JJ;Crystal JS;Roberts IM;Trebska-McGowan K;Wunderlich JR;Yang JC;Rosenberg SA
通讯作者：
Rosenberg SA
DOI：
10.1158/1078-0432.ccr-17-3099
发表时间：
2018-03-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Hu ZI;Shia J;Stadler ZK;Varghese AM;Capanu M;Salo-Mullen E;Lowery MA;Diaz LA Jr;Mandelker D;Yu KH;Zervoudakis A;Kelsen DP;Iacobuzio-Donahue CA;Klimstra DS;Saltz LB;Sahin IH;O'Reilly EM
通讯作者：
O'Reilly EM
影响因子：
16.6
作者：
Hall MP;Woodroofe CC;Wood MG;Que I;Van't Root M;Ridwan Y;Shi C;Kirkland TA;Encell LP;Wood KV;Löwik C;Mezzanotte L
通讯作者：
Mezzanotte L