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.

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。