Elimination of oncogenic KRAS in genetic mouse models eradicates pancreatic cancer by inducing FAS-dependent apoptosis by CD8+ T cells

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

doi:10.1016/j.devcel.2023.07.025

Elimination of oncogenic KRAS in genetic mouse models eradicates pancreatic cancer by inducing FAS-dependent apoptosis by CD8⁺ T cells

Dev Cell. 2023 Sep 11;58(17):1562-1577.e8. doi: 10.1016/j.devcel.2023.07.025. Epub 2023 Aug 24.

Authors

Krishnan K Mahadevan¹, Valerie S LeBleu², Elena V Ramirez¹, Yang Chen¹, Bingrui Li¹, Amari M Sockwell¹, Mihai Gagea³, Hikaru Sugimoto¹, Lakshmi Kavitha Sthanam¹, Desiree Tampe⁴, Michael Zeisberg⁴, Haoqiang Ying⁵, Abhinav K Jain⁶, Ronald A DePinho¹, Anirban Maitra⁷, Kathleen M McAndrews¹, Raghu Kalluri⁸

Affiliations

¹ Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
² 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.
³ Department of Veterinary Medicine and Surgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁴ Department of Nephrology and Rheumatology, Göttingen University Medical Center, Georg August University, Göttingen, Germany.
⁵ Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁶ Department of Epigenetics and Molecular Carcinogenesis, Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁷ Department of Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁸ Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Bioengineering, Rice University, Houston, TX, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. Electronic address: rkalluri@mdanderson.org.

Abstract

Oncogenic KRAS^G12D (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: CD8(+) T cells; FAS-FASL; KRAS(G12D); oncogenic KRAS; pancreatic cancer.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
CD8-Positive T-Lymphocytes
Carcinoma, Pancreatic Ductal* / genetics
Epigenesis, Genetic
Humans
Mice
Pancreatic Neoplasms* / genetics
Proto-Oncogene Proteins p21(ras)* / genetics

Substances

Proto-Oncogene Proteins p21(ras)
Hras protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding