Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
Dev Cell. 2023 Sep 11;58(17):1562-1577.e8. doi: 10.1016/j.devcel.2023.07.025. Epub 2023 Aug 24.
Oncogenic KRAS (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.
致癌性 KRAS（KRAS）对于胰腺导管腺癌（PDAC）的发生和维持至关重要，并且是肿瘤免疫的已知抑制剂。在 PDAC 的遗传小鼠模型中条件性消除 KRAS 会导致 FAS 的重新激活、CD8 T 细胞介导的细胞凋亡以及肿瘤的完全消除。KRAS 的消除会招募激活的 CD4 和 CD8 T 细胞，并促进抗原呈递细胞的激活。从机制上讲，KRAS 介导的免疫逃避涉及通过其启动子区域的甲基化来调节癌细胞中 Fas 死亡受体的表观遗传。此外，对人类 RNA 测序的分析表明，PDAC 肿瘤中高 KRAS 表达与低 KRAS 表达的肿瘤相比，显示出较低比例的 CD8 T 细胞，并且生存时间更短。这项研究强调了在消除 KRAS 后 CD8 T 细胞在消灭 PDAC 中的作用，并为 KRAS 靶向治疗与免疫疗法联合控制 PDAC 提供了依据。
