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Phenotypic Switching of Naïve T Cells to Immune-Suppressive Treg-Like Cells by Mutant KRAS

Arjun Kalvala1, Pierre Wallet2, Lu Yang3

  • 1Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA. akalvala@coh.org.

Journal of Clinical Medicine
|October 23, 2019
PubMed

Insights

Mutant KRAS in non-small-cell lung cancer (NSCLC) causes immune-suppressive T cells. This study reveals a new mechanism for KRAS in T cell changes, offering a novel therapeutic target for NSCLC.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Mutant Kirsten rat sarcoma viral oncogene homolog (KRAS) drives cancer progression through uncontrolled cell proliferation and altered metabolism.
  • The role of KRAS in modulating the tumor microenvironment and immune cell function is not fully understood.

Purpose of the Study:

  • To investigate the cell-extrinsic effects of mutant KRAS on T cell phenotype and function.
  • To identify the underlying molecular mechanisms of KRAS-mediated T cell modulation in non-small-cell lung cancer (NSCLC).

Main Methods:

  • Incubation of CD4+ T cells with tumor-derived exosomes, patient sera, and xenograft models from mutant KRAS NSCLC.
  • Genetic manipulation of T cells with mutant KRAS cDNA.
  • Single-cell sequencing and mathematical modeling to elucidate the mechanism.

Main Results:

  • Exposure to mutant KRAS-associated factors induced a phenotypic conversion of CD4+ T cells to FOXP3+ regulatory T cell (Treg)-like, immune-suppressive cells.
  • Direct transfection of T cells with mutant KRAS cDNA replicated this phenotypic switch.
  • Single-cell sequencing identified the interferon pathway as the key mediator of this KRAS-induced T cell transformation.

Conclusions:

  • Mutant KRAS exerts a novel, cytokine-independent, cell-extrinsic influence on T cell phenotype, promoting immune suppression.
  • Targeting this KRAS-induced Treg-like cell population presents a promising therapeutic strategy for NSCLC.
  • The findings have broad implications for KRAS-mutated cancers due to KRAS's frequent mutation across various malignancies.
Keywords:
FOXP3KRASTregscell-extrinsiclung cancerphenotypic switching

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