Kalvala, Arjun and Wallet, Pierre and Yang, Lu and Wang, Chongkai and Li, Haiqing and Nam, Arin and Nathan, Anusha and Mambetsariev, Isa and Poroyko, Valeriy and Gao, Hanlin and Chu, Peiguo and Sattler, Martin and Bild, Andrea and Manuel, Edwin R and Lee, Peter P and Jolly, Mohit Kumar and Kulkarni, Prakash and Salgia, Ravi (2019) Phenotypic Switching of Naïve T Cells to Immune-Suppressive Treg-Like Cells by Mutant KRAS. In: Journal of Clinical Medicine, 8 (10). ISSN 2077-0383
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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.
| Item Type: | Journal Article |
|---|---|
| Publication: | Journal of Clinical Medicine |
| Publisher: | MDPI |
| Additional Information: | Copyright of this article belongs to MDPI |
| Keywords: | KRAS; cell-extrinsic; Tregs; lung cancer; FOXP3; phenotypic switching |
| Department/Centre: | Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering |
| Date Deposited: | 20 Dec 2019 09:59 |
| Last Modified: | 20 Dec 2019 09:59 |
| URI: | http://eprints.iisc.ac.in/id/eprint/64180 |
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