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Open AccessArticle

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

1
Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA
2
Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
3
Center for Informatics, City of Hope National Medical Center, Duarte, CA 91010, USA
4
Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
5
Fulgent Genetics, 4978 Santa Anita Avenue, Temple City, CA 91780, USA
6
Department of Pathology, City of Hope National Medical Center, Duarte, CA 91010, USA
7
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
8
Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA 91010, USA
9
Department of Immuno-Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA
10
Center for BioSystems Science and Engineering, Indian Institute of Science, 560012 Bangalore, India
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2019, 8(10), 1726; https://doi.org/10.3390/jcm8101726
Received: 12 September 2019 / Revised: 9 October 2019 / Accepted: 15 October 2019 / Published: 18 October 2019
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. View Full-Text
Keywords: KRAS; cell-extrinsic; Tregs; lung cancer; FOXP3; phenotypic switching KRAS; cell-extrinsic; Tregs; lung cancer; FOXP3; phenotypic switching
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Kalvala, A.; Wallet, P.; Yang, L.; Wang, C.; Li, H.; Nam, A.; Nathan, A.; Mambetsariev, I.; Poroyko, V.; Gao, H.; Chu, P.; Sattler, M.; Bild, A.; Manuel, E.R.; Lee, P.P.; Jolly, M.K.; Kulkarni, P.; Salgia, R. Phenotypic Switching of Naïve T Cells to Immune-Suppressive Treg-Like Cells by Mutant KRAS. J. Clin. Med. 2019, 8, 1726.

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