Phenotypic Switching of Naïve T Cells to Immune-Suppressive Treg-Like Cells by Mutant KRAS
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:8 |
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| Enthalten in: |
Journal of clinical medicine - 8(2019), 10 vom: 18. Okt. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kalvala, Arjun [VerfasserIn] |
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| Links: |
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| Themen: |
Cell-extrinsic |
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| Anmerkungen: |
Date Revised 28.09.2020 published: Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.3390/jcm8101726 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM302415688 |
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| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a lung cancer | |
| 650 | 4 | |a phenotypic switching | |
| 700 | 1 | |a Wallet, Pierre |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Lu |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Chongkai |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Haiqing |e verfasserin |4 aut | |
| 700 | 1 | |a Nam, Arin |e verfasserin |4 aut | |
| 700 | 1 | |a Nathan, Anusha |e verfasserin |4 aut | |
| 700 | 1 | |a Mambetsariev, Isa |e verfasserin |4 aut | |
| 700 | 1 | |a Poroyko, Valeriy |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Hanlin |e verfasserin |4 aut | |
| 700 | 1 | |a Chu, Peiguo |e verfasserin |4 aut | |
| 700 | 1 | |a Sattler, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Bild, Andrea |e verfasserin |4 aut | |
| 700 | 1 | |a Manuel, Edwin R |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Peter P |e verfasserin |4 aut | |
| 700 | 1 | |a Jolly, Mohit Kumar |e verfasserin |4 aut | |
| 700 | 1 | |a Kulkarni, Prakash |e verfasserin |4 aut | |
| 700 | 1 | |a Salgia, Ravi |e verfasserin |4 aut | |
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