Elimination of Oncogenic Kras in Genetic Mouse Models Eradicates Pancreatic Cancer by Inducing Fas-Dependent Apoptosis by CD8+ T cells

Authors

Krishnan K Mahadevan
Valerie S LeBleu
Elena V Ramirez
Yang Chen
Bingrui Li
Amari M Sockwell
Mihai Gagea
Hikaru Sugimoto
Lakshmi Kavitha Sthanam
Desiree Tampe
Michael Zeisberg
Haoqiang Ying
Abhinav K Jain
Ronald A DePinho
Anirban Maitra
Kathleen M McAndrews
Raghu Kalluri

Publication Date

9-11-2023

Journal

Develpmental Cell

Abstract

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.

Keywords

Animals, Humans, Mice, Apoptosis, Carcinoma, Pancreatic Ductal, CD8-Positive T-Lymphocytes, Epigenesis, Genetic, Pancreatic Neoplasms, Proto-Oncogene Proteins p21(ras), KRAS, pancreatic cancer, FAS-FASL, CD8+T Cells, oncogenic KRAS

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Associated Data

PMID: 37625403