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

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.

doi:10.1101/763912

bioRxiv · 10.1101/763912

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

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.

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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.

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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.. 2019-09-11. Phenotypic Switching of Naïve T cells to Immune-suppressive Treg-like Cells by Mutant KRAS. https://doi.org/10.1101/763912

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