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

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

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1562-1577.e8
Journal	Developmental cell
Volume	58
Issue number	17
DOIs	https://doi.org/10.1016/j.devcel.2023.07.025
State	Published - Sep 11 2023

Keywords

CD8 T cells
FAS-FASL
KRAS
oncogenic KRAS
pancreatic cancer

ASJC Scopus subject areas

Molecular Biology
General Biochemistry, Genetics and Molecular Biology
Developmental Biology
Cell Biology

MD Anderson CCSG core facilities

Research Animal Support Facility
Advanced Technology Genomics Core
Epigenomics Profiling Core Facility
Genetically Engineered Mouse Facility
Flow Cytometry and Cellular Imaging Facility
Small Animal Imaging Facility

Access to Document

10.1016/j.devcel.2023.07.025

Cite this

Mahadevan, K. K., LeBleu, V. S., Ramirez, E. V., Chen, Y., Li, B., Sockwell, A. M., Gagea, M., Sugimoto, H., Sthanam, L. K., Tampe, D., Zeisberg, M., Ying, H., Jain, A. K., DePinho, R. A., Maitra, A., McAndrews, K. M., & Kalluri, R. (2023). Elimination of oncogenic KRAS in genetic mouse models eradicates pancreatic cancer by inducing FAS-dependent apoptosis by CD8⁺ T cells. Developmental cell, 58(17), 1562-1577.e8. https://doi.org/10.1016/j.devcel.2023.07.025

Mahadevan, KK, LeBleu, VS, Ramirez, EV, Chen, Y, Li, B, Sockwell, AM, Gagea, M , Sugimoto, H, Sthanam, LK, Tampe, D, Zeisberg, M, Ying, H , Jain, AK , DePinho, RA , Maitra, A , McAndrews, KM & Kalluri, R 2023, 'Elimination of oncogenic KRAS in genetic mouse models eradicates pancreatic cancer by inducing FAS-dependent apoptosis by CD8⁺ T cells', Developmental cell, vol. 58, no. 17, pp. 1562-1577.e8. https://doi.org/10.1016/j.devcel.2023.07.025

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

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 = "CD8 T cells, FAS-FASL, KRAS, oncogenic KRAS, pancreatic cancer",

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

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T1 - Elimination of oncogenic KRAS in genetic mouse models eradicates pancreatic cancer by inducing FAS-dependent apoptosis by CD8+ T cells

AU - Mahadevan, Krishnan K.

AU - LeBleu, Valerie S.

AU - Ramirez, Elena V.

AU - Chen, Yang

AU - Li, Bingrui

AU - Sockwell, Amari M.

AU - Gagea, Mihai

AU - Sugimoto, Hikaru

AU - Sthanam, Lakshmi Kavitha

AU - Tampe, Desiree

AU - Zeisberg, Michael

AU - Ying, Haoqiang

AU - Jain, Abhinav K.

AU - DePinho, Ronald A.

AU - Maitra, Anirban

AU - McAndrews, Kathleen M.

AU - Kalluri, Raghu

PY - 2023/9/11

Y1 - 2023/9/11

N2 - 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.

AB - 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.

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