Mutant KRAS Conversion of Conventional T Cells into Regulatory T Cells

Stephanie Zdanov, Magis Mandapathil, Rasha Abu Eid, Saudat Adamson-Fadeyi, Willie Wilson, Jiahua Qian, Andrea Carnie, Nadya Tarasova, Mikayel Mkrtichyan, Jay A Berzofsky, Theresa L Whiteside, Samir N Khleif

Research output: Contribution to journalArticlepeer-review

41 Citations (Scopus)

Abstract

Constitutive activation of the KRAS oncogene in human malignancies is associated with aggressive tumor growth and poor prognosis. Similar to other oncogenes, KRAS acts in a cell-intrinsic manner to affect tumor growth or survival. However, we describe here a different, cell-extrinsic mechanism through which mutant KRAS contributes to tumor development. Tumor cells carrying mutated KRAS induced highly suppressive T cells, and silencing KRAS reversed this effect. Overexpression of the mutant KRAS(G12V)gene in wild-type KRAS tumor cells led to regulatory T-cell (Treg) induction. We also demonstrate that mutant KRAS induces the secretion of IL10 and transforming growth factor-β1 (both required for Treg induction) by tumor cells through the activation of the MEK-ERK-AP1 pathway. Finally, we report that inhibition of KRAS reduces the infiltration of Tregs in KRAS-driven lung tumorigenesis even before tumor formation. This cell-extrinsic mechanism allows tumor cells harboring a mutant KRAS oncogene to escape immune recognition. Thus, an oncogene can promote tumor progression independent of its transforming activity by increasing the number and function of Tregs. This has a significant clinical potential, in which targeting KRAS and its downstream signaling pathways could be used as powerful immune modulators in cancer immunotherapy.

Original languageEnglish
Pages (from-to)354-365
Number of pages12
JournalCancer immunology research
Volume4
Issue number4
DOIs
Publication statusPublished - Apr 2016

Keywords

  • Research Support, N.I.H., Intramural

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