title: Mutant KRAS Conversion of Conventional T Cells into Regulatory T Cells.
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.
authors.affiliation: Cancer Vaccine Section, Vaccine Branch, NCI, Center for Cancer Research, NIH, Bethesda, Maryland.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Zdanov
authors.affiliation: Department of Pathology, IMPCL, University of Pittsburgh Cancer Institute (UPCI), Pittsburg, Pennsylvania.
authors.forename: Magis
authors.initials: M
authors.lastname: Mandapathil
authors.affiliation: Cancer Vaccine Section, Vaccine Branch, NCI, Center for Cancer Research, NIH, Bethesda, Maryland. Georgia Cancer Center, Augusta University (previously Georgia Regents University), Augusta, Georgia.
authors.forename: Rasha
authors.initials: R
authors.lastname: Abu Eid
authors.affiliation: Cancer Vaccine Section, Vaccine Branch, NCI, Center for Cancer Research, NIH, Bethesda, Maryland.
authors.forename: Saudat
authors.initials: S
authors.lastname: Adamson-Fadeyi
authors.affiliation: Medical Oncology Branch, Center for Cancer Research, NCI, Bethesda, Maryland.
authors.forename: Willie
authors.initials: W
authors.lastname: Wilson
authors.affiliation: Cancer Vaccine Section, Vaccine Branch, NCI, Center for Cancer Research, NIH, Bethesda, Maryland.
authors.forename: Jiahua
authors.initials: J
authors.lastname: Qian
authors.affiliation: Cancer Vaccine Section, Vaccine Branch, NCI, Center for Cancer Research, NIH, Bethesda, Maryland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Carnie
authors.affiliation: Cancer and Inflammation Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland.
authors.forename: Nadya
authors.initials: N
authors.lastname: Tarasova
authors.affiliation: Cancer Vaccine Section, Vaccine Branch, NCI, Center for Cancer Research, NIH, Bethesda, Maryland. Georgia Cancer Center, Augusta University (previously Georgia Regents University), Augusta, Georgia.
authors.forename: Mikayel
authors.initials: M
authors.lastname: Mkrtichyan
authors.affiliation: Molecular Immunogenetics and Vaccine Research Section, Vaccine Branch, Center for Cancer Research, NIH, Bethesda, Maryland.
authors.forename: Jay A
authors.initials: JA
authors.lastname: Berzofsky
authors.affiliation: Department of Pathology, IMPCL, University of Pittsburgh Cancer Institute (UPCI), Pittsburg, Pennsylvania.
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Whiteside
authors.affiliation: Cancer Vaccine Section, Vaccine Branch, NCI, Center for Cancer Research, NIH, Bethesda, Maryland. Georgia Cancer Center, Augusta University (previously Georgia Regents University), Augusta, Georgia. SKHLEIF@gru.edu.
authors.forename: Samir N
authors.initials: SN
authors.lastname: Khleif
mesh_terms: D000818:Animals; D015415:Biomarkers; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000378:metabolism; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009154:Mutation; D010641:Phenotype; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics*
chemical_list: D015415:Biomarkers; D018808:Transcription Factor AP-1; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins