致癌基因KRASG12D（KRAS∗）对胰腺导管癌（PDAC）的形成和维持至关重要，并已知为肿瘤免疫的抑制剂。在PDAC的遗传小鼠模型中有条件地消除KRAS∗会导致FAS的重新活化、CD8+T细胞介导的凋亡以及肿瘤的完全根除。KRAS∗的消除有助于激活CD4+和CD8+T细胞，并促进抗原递呈细胞的激活。从机制上讲，KRAS∗介导的免疫逃避涉及通过甲基化其启动子区域对癌细胞中Fas死亡受体的表观遗传调控。此外，对人体RNA测序的分析显示，在PDAC肿瘤中KRAS表达高的病例中的CD8+T细胞比例较低，并且生存期较短，与KRAS表达低的肿瘤相比。本研究强调了CD8 + T细胞在KRAS∗消除后根除PDAC中的作用，并为将KRAS∗靶向治疗与免疫疗法结合控制PDAC提供了合理依据。版权所有 © 2023 Elsevier Inc. 保留所有权利。

Oncogenic KRASG12D (KRAS∗) is critical for the initiation and maintenance of pancreatic ductal adenocarcinoma (PDAC) and is a known repressor of tumor immunity. Conditional elimination of KRAS∗ in genetic mouse models of PDAC leads to the reactivation of FAS, CD8+ T cell-mediated apoptosis, and complete eradication of tumors. KRAS∗ elimination recruits activated CD4+ and CD8+ T cells and promotes the activation of antigen-presenting cells. Mechanistically, KRAS∗-mediated immune evasion involves the epigenetic regulation of Fas death receptor in cancer cells, via methylation of its promoter region. Furthermore, analysis of human RNA sequencing identifies that high KRAS expression in PDAC tumors shows a lower proportion of CD8+ T cells and demonstrates shorter survival compared with tumors with low KRAS expression. This study highlights the role of CD8+ T cells in the eradication of PDAC following KRAS∗ elimination and provides a rationale for the combination of KRAS∗ targeting with immunotherapy to control PDAC.Copyright © 2023 Elsevier Inc. All rights reserved.