1. Phenotypic Switching of Naïve T Cells to Immune-Suppressive Treg-Like Cells by Mutant KRAS.
- Author
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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, and Salgia, Ravi
- Subjects
FOXP3 ,KRAS ,Tregs ,cell-extrinsic ,lung cancer ,phenotypic switching ,Clinical Sciences - 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.
- Published
- 2019