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 journalArticle

33 Scopus citations

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 KRASG12V 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-b1 (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 (US)
Pages (from-to)354-365
Number of pages12
JournalCancer Immunology Research
Volume4
Issue number4
DOIs
StatePublished - 2016

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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  • Cite this

    Zdanov, S., Mandapathil, M., Eid, R. A., Adamson-Fadeyi, S., Wilson, W., Qian, J., Carnie, A., Tarasova, N., Mkrtichyan, M., Berzofsky, J. A., Whiteside, T. L., & Khleif, S. N. (2016). Mutant KRAS conversion of conventional T cells into regulatory T cells. Cancer Immunology Research, 4(4), 354-365. https://doi.org/10.1158/2326-6066.CIR-15-0241