Phenotypic Switching of Naïve T cells to Immune-suppressive Treg-like Cells by Mutant KRAS
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..
| Medienart: |
|
|---|
Preprint| Erscheinungsjahr: |
2021 |
|---|---|
| Erschienen: |
2021 |
| Enthalten in: |
bioRxiv.org - (2021) vom: 20. Jan. Zur Gesamtaufnahme - year:2021 |
|---|
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Kalvala, Arjun [VerfasserIn] |
|---|
| Links: |
|---|
| doi: |
10.1101/763912 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
XBI000614289 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | XBI000614289 | ||
| 003 | DE-627 | ||
| 005 | 20230429091538.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 200312s2021 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1101/763912 |2 doi | |
| 035 | |a (DE-627)XBI000614289 | ||
| 035 | |a (DE-599)biorXiv10.1101/763912 | ||
| 035 | |a (biorXiv)10.1101/763912 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 082 | 0 | |a 570 |q DE-84 | |
| 100 | 1 | |a Kalvala, Arjun |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Phenotypic Switching of Naïve T cells to Immune-suppressive Treg-like Cells by Mutant KRAS |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 520 | |a 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. | ||
| 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 | |
| 773 | 0 | 8 | |i Enthalten in |t bioRxiv.org |g (2021) vom: 20. Jan. |
| 773 | 1 | 8 | |g year:2021 |g day:20 |g month:01 |
| 856 | 4 | 0 | |u https://doi.org/10.3390/jcm8101726 |z lizenzpflichtig |3 Volltext |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1101/763912 |z kostenfrei |3 Volltext |
| 912 | |a GBV_XBI | ||
| 912 | |a SSG-OLC-PHA | ||
| 951 | |a AR | ||
| 952 | |j 2021 |b 20 |c 01 | ||
| 953 | |2 045F |a 570 | ||