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Open Access Publications from the University of California

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

  • Author(s): Kalvala, Arjun
  • Wallet, Pierre
  • Yang, Lu
  • Wang, Chongkai
  • Li, Haiqing
  • Nam, Arin
  • Nathan, Anusha
  • Mambetsariev, Isa
  • Poroyko, Valeriy
  • Gao, Hanlin
  • Chu, Peiguo
  • Sattler, Martin
  • Bild, Andrea
  • Manuel, Edwin R
  • Lee, Peter P
  • Jolly, Mohit Kumar
  • Kulkarni, Prakash
  • Salgia, Ravi
  • et al.
Abstract

Oncogenic (mutant) Ras protein Kirsten rat sarcoma viral oncogene homolog (KRAS) promotes uncontrolled proliferation, altered metabolism, and loss of genome integrity in a cell-intrinsic manner. Here, we demonstrate that CD4+ T cells when incubated with tumor-derived exosomes from mutant (MT) KRAS non-small-cell lung cancer (NSCLC) cells, patient sera, or a mouse xenograft model, induce phenotypic conversion to FOXP3+ Treg-like cells that are immune-suppressive. Furthermore, transfecting T cells with MT KRAS cDNA alone induced phenotypic switching and mathematical modeling supported this conclusion. Single-cell sequencing identified the interferon pathway as the mechanism underlying the phenotypic switch. These observations highlight a novel cytokine-independent, cell-extrinsic role for KRAS in T cell phenotypic switching. Thus, targeting this new class of Tregs represents a unique therapeutic approach for NSCLC. Since KRAS is the most frequently mutated oncogene in a wide variety of cancers, the findings of this investigation are likely to be of broad interest and have a large scientific impact.

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