Faculty, Staff and Student Publications
Publication Date
9-11-2023
Journal
Developmental Cell
DOI
10.1016/j.devcel.2023.07.025
PMID
37625403
PMCID
PMC10810082
PubMedCentral® Posted Date
9-11-2024
PubMedCentral® Full Text Version
Author MSS
Abstract
Oncogenic KrasG12D (Kras*) is critical for the initiation and maintenance of pancreatic ductal adenocarcinoma (PDAC), and a known repressor of tumor immunity. Conditional elimination of Kras* in genetic mouse models of PDAC leads to 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 epigenetic regulation of the Fas death receptor in cancer cells, via methylation of its promoter region. Further, analysis of human RNA sequencing identifies that high KRAS expressing PDAC tumors show a lower proportion of CD8+ T cells and demonstrate shorter survival compared to patients with low KRAS expression. This study highlights the role of CD8+ T cells in eradication of PDAC following Kras* elimination and provides rationale for 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)
Published Open-Access
yes
Recommended Citation
Mahadevan, Krishnan K; LeBleu, Valerie S; Ramirez, Elena V; et al., "Elimination of Oncogenic Kras in Genetic Mouse Models Eradicates Pancreatic Cancer by Inducing Fas-Dependent Apoptosis by CD8+ T Cells" (2023). Faculty, Staff and Student Publications. 4535.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4535
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