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Mutant KRAS Conversion of Conventional T Cells into Regulatory T Cells

Stephanie Zdanov1, Magis Mandapathil2, Rasha Abu Eid3

  • 1Cancer Vaccine Section, Vaccine Branch, NCI, Center for Cancer Research, NIH, Bethesda, Maryland.

Cancer Immunology Research
|February 17, 2016
PubMed

Insights

Mutant KRAS oncogenes promote tumor growth by inducing suppressive T cells, a novel cell-extrinsic mechanism. Targeting KRAS could enhance cancer immunotherapy by modulating these immune cells.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Constitutive KRAS oncogene activation drives aggressive human cancers.
  • KRAS typically functions intrinsically to promote tumor growth and survival.
  • A novel cell-extrinsic mechanism of KRAS oncogene action in tumorigenesis is investigated.

Purpose of the Study:

  • To elucidate the cell-extrinsic mechanisms by which mutant KRAS contributes to tumor development.
  • To investigate the role of KRAS in modulating the tumor immune microenvironment.
  • To explore the potential of targeting KRAS as an immunomodulatory strategy in cancer therapy.

Main Methods:

  • Overexpression of mutant KRAS(G12V) in wild-type KRAS tumor cells.
  • Analysis of regulatory T-cell (Treg) induction and cytokine secretion (IL-10, TGF-β1).
  • Investigation of the MEK-ERK-AP1 signaling pathway activation.
  • Assessment of Treg infiltration in KRAS-driven lung tumorigenesis following KRAS inhibition.

Main Results:

  • Mutant KRAS-expressing tumor cells induce highly suppressive T cells; KRAS silencing reverses this effect.
  • Overexpression of mutant KRAS(G12V) induces regulatory T-cell (Treg) expansion.
  • Mutant KRAS activates the MEK-ERK-AP1 pathway, leading to IL-10 and TGF-β1 secretion, crucial for Treg induction.
  • KRAS inhibition reduces Treg infiltration in early-stage KRAS-driven lung cancer.

Conclusions:

  • Mutant KRAS promotes tumor progression via a cell-extrinsic mechanism by increasing Treg numbers and function, facilitating immune escape.
  • This oncogene-driven immune suppression is independent of KRAS's intrinsic transforming activity.
  • Targeting KRAS and its downstream pathways offers significant potential as immune modulators in cancer immunotherapy.

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