KRASG12D抑制可重新调控早期和晚期胰腺癌的微环境，以促进CD8+ T细胞通过FAS介导的杀伤作用。
KRASG12D inhibition reprograms the microenvironment of early and advanced pancreatic cancer to promote FAS-mediated killing by CD8+ T cells.
发表日期：2023 Aug 23
作者：
Krishnan K Mahadevan, Kathleen M McAndrews, Valerie S LeBleu, Sujuan Yang, Hengyu Lyu, Bingrui Li, Amari M Sockwell, Michelle L Kirtley, Sami J Morse, Barbara A Moreno Diaz, Michael P Kim, Ningping Feng, Anastasia M Lopez, Paola A Guerrero, Francesca Paradiso, Hikaru Sugimoto, Kent A Arian, Haoqiang Ying, Yasaman Barekatain, Lakshmi Kavitha Sthanam, Patience J Kelly, Anirban Maitra, Timothy P Heffernan, Raghu Kalluri
来源：
CANCER CELL
摘要：
KRASG12D突变在近半数胰腺腺癌（PDAC）中存在。我们研究了使用MRTX1133这种非共价小分子抑制剂抑制KRASG12D突变蛋白对早期和晚期PDAC的影响，以及其对肿瘤微环境的影响。我们使用了16个不同模型的KRASG12D驱动PDAC进行实验，证明MRTX1133逆转早期PDAC的生长，增加肿瘤内CD8+效应T细胞，减少髓系细胞浸润，并重编程癌相关成纤维细胞。MRTX1133能够使早期和晚期PDAC的PanIN（胰内部囊性病变）均发生消退。晚期PDAC的消退需要CD8+ T细胞，并且免疫检查点阻断（ICB）与MRTX1133相辅相成，能够根除PDAC并延长总生存期。从机理上讲，抑制KRASG12D在晚期PDAC和人源器官样体外培养物中诱导FAS在癌细胞中的表达，并促进CD8+ T细胞介导的细胞死亡。总体上，该研究为MRTX1133与ICB在临床试验中的协同联合提供了理论依据。版权所有©2023 Elsevier Inc. 保留所有权利。
The KRASG12D mutation is present in nearly half of pancreatic adenocarcinomas (PDAC). We investigated the effects of inhibiting the KRASG12D mutant protein with MRTX1133, a non-covalent small molecule inhibitor of KRASG12D, on early and advanced PDAC and its influence on the tumor microenvironment. Employing 16 different models of KRASG12D-driven PDAC, we demonstrate that MRTX1133 reverses early PDAC growth, increases intratumoral CD8+ effector T cells, decreases myeloid infiltration, and reprograms cancer-associated fibroblasts. MRTX1133 leads to regression of both established PanINs and advanced PDAC. Regression of advanced PDAC requires CD8+ T cells and immune checkpoint blockade (ICB) synergizes with MRTX1133 to eradicate PDAC and prolong overall survival. Mechanistically, inhibition of KRASG12D in advanced PDAC and human patient derived organoids induces FAS expression in cancer cells and facilitates CD8+ T cell-mediated death. Collectively, this study provides a rationale for a synergistic combination of MRTX1133 with ICB in clinical trials.Copyright © 2023 Elsevier Inc. All rights reserved.