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The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer
Cancer Cell ( IF 48.8 ) Pub Date : 2021-08-05 , DOI: 10.1016/j.ccell.2021.07.007
William A Freed-Pastor 1 , Laurens J Lambert 2 , Zackery A Ely 2 , Nimisha B Pattada 3 , Arjun Bhutkar 3 , George Eng 4 , Kim L Mercer 3 , Ana P Garcia 3 , Lin Lin 3 , William M Rideout 3 , William L Hwang 5 , Jason M Schenkel 6 , Alex M Jaeger 3 , Roderick T Bronson 3 , Peter M K Westcott 3 , Tyler D Hether 7 , Prajan Divakar 7 , Jason W Reeves 7 , Vikram Deshpande 8 , Toni Delorey 9 , Devan Phillips 9 , Omer H Yilmaz 10 , Aviv Regev 11 , Tyler Jacks 2
Affiliation  

The CD155/TIGIT axis can be co-opted during immune evasion in chronic viral infections and cancer. Pancreatic adenocarcinoma (PDAC) is a highly lethal malignancy, and immune-based strategies to combat this disease have been largely unsuccessful to date. We corroborate prior reports that a substantial portion of PDAC harbors predicted high-affinity MHC class I-restricted neoepitopes and extend these findings to advanced/metastatic disease. Using multiple preclinical models of neoantigen-expressing PDAC, we demonstrate that intratumoral neoantigen-specific CD8+ T cells adopt multiple states of dysfunction, resembling those in tumor-infiltrating lymphocytes of PDAC patients. Mechanistically, genetic and/or pharmacologic modulation of the CD155/TIGIT axis was sufficient to promote immune evasion in autochthonous neoantigen-expressing PDAC. Finally, we demonstrate that the CD155/TIGIT axis is critical in maintaining immune evasion in PDAC and uncover a combination immunotherapy (TIGIT/PD-1 co-blockade plus CD40 agonism) that elicits profound anti-tumor responses in preclinical models, now poised for clinical evaluation.



中文翻译:


CD155/TIGIT 轴促进并维持表达新抗原的胰腺癌的免疫逃避



CD155/TIGIT 轴可以在慢性病毒感染和癌症的免疫逃避过程中被选择。胰腺癌(PDAC)是一种高度致命的恶性肿瘤,迄今为止,基于免疫的策略来对抗这种疾病基本上不成功。我们证实了之前的报道,即 PDAC 的很大一部分含有预测的高亲和力 MHC I 类限制性新表位,并将这些发现扩展到晚期/转移性疾病。使用表达新抗原的 PDAC 的多个临床前模型,我们证明肿瘤内新抗原特异性 CD8 + T 细胞呈现多种功能障碍状态,类似于 PDAC 患者肿瘤浸润淋巴细胞的状态。从机制上讲,CD155/TIGIT 轴的遗传和/或药理学调节足以促进表达新抗原的 PDAC 的免疫逃避。最后,我们证明 CD155/TIGIT 轴对于维持 PDAC 的免疫逃避至关重要,并发现了一种联合免疫疗法(TIGIT/PD-1 共同阻断加 CD40 激动),该疗法在临床前模型中引发深刻的抗肿瘤反应,现已准备好临床评价。

更新日期:2021-10-11
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