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Phenotypic Switching of Naïve T cells to Immune-suppressive Treg-like Cells by Mutant KRAS

By Arjun Kalvala, Pierre Wallet, Lu Yang, Chongkai Wang, Haiqing Li, Arin Nam, Anusha Nathan, Isa Mambetsariev, Valeriy Poroyko, Hanlin Gao, Peiguo Chu, Martin Sattler, Andrea Bild, Edwin R Manuel, Peter P Lee, Mohit Kumar Jolly, Prakash Kulkarni, Ravi Salgia

Posted 11 Sep 2019
bioRxiv DOI: 10.1101/763912 (published DOI: 10.3390/jcm8101726)

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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