Mutant KRAS Conversion of Conventional T Cells into Regulatory T Cells

• Published in: Cancer immunology research Vol. 4; no. 4; p. 354
• Main Authors: Zdanov, Stephanie, Mandapathil, Magis, Abu Eid, Rasha, Adamson-Fadeyi, Saudat, Wilson, Willie, Qian, Jiahua, Carnie, Andrea, Tarasova, Nadya, Mkrtichyan, Mikayel, Berzofsky, Jay A, Whiteside, Theresa L, Khleif, Samir N
• Format: Journal Article
• Language: English
• Published: United States 01.04.2016
• Subjects: Animals; Biomarkers; Cell Line, Tumor; Cell Transformation, Neoplastic - genetics; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases - metabolism; Humans; Immunophenotyping; Interleukin-10 - metabolism; Lung Neoplasms - immunology; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Mice; Mutation; Phenotype; ras Proteins - genetics; Signal Transduction; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Transcription Factor AP-1 - metabolism; Transforming Growth Factor beta1 - metabolism
• ISSN: 2326-6074
• DOI: 10.1158/2326-6066.CIR-15-0241

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.