Small Molecule Inhibitors of MERTK and FLT3 Induce Cell Cycle Arrest in Human CD8<sup>+</sup> T Cells
There is an increasing interest in the development of Receptor Tyrosine Kinases inhibitors (RTKIs) for cancer treatment, as dysregulation of RTK expression can govern oncogenesis. Among the newer generations of RTKIs, many target Mer Tyrosine Kinase (MERTK) and Fms related RTK 3 (FLT3). Next to bein...
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MDPI AG
2021
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oai:doaj.org-article:ea4b29a1d4364e7390284cee2fd8917d2021-11-25T19:11:00ZSmall Molecule Inhibitors of MERTK and FLT3 Induce Cell Cycle Arrest in Human CD8<sup>+</sup> T Cells10.3390/vaccines91112942076-393Xhttps://doaj.org/article/ea4b29a1d4364e7390284cee2fd8917d2021-11-01T00:00:00Zhttps://www.mdpi.com/2076-393X/9/11/1294https://doaj.org/toc/2076-393XThere is an increasing interest in the development of Receptor Tyrosine Kinases inhibitors (RTKIs) for cancer treatment, as dysregulation of RTK expression can govern oncogenesis. Among the newer generations of RTKIs, many target Mer Tyrosine Kinase (MERTK) and Fms related RTK 3 (FLT3). Next to being overexpressed in many cancers, MERTK and FLT3 have important roles in immune cell development and function. In this study, we address how the new generation and potent RTKIs of MERTK/FLT3 affect human primary CD8<sup>+</sup> T cell function. Using ex vivo T cell receptor (TCR)-activated CD8<sup>+</sup> T cells, we demonstrate that use of dual MERTK/FLT3 inhibitor UNC2025 restricts CD8<sup>+</sup> T proliferation at the G2 phase, at least in part by modulation of mTOR signaling. Cytokine production and activation remain largely unaffected. Finally, we show that activated CD8<sup>+</sup> T cells express FLT3 from day two post activation, and FLT3 inhibition with AC220 (quizartinib) or siRNA-mediated knockdown affects cell cycle kinetics. These results signify that caution is needed when using potent RTKIs in the context of antitumor immune responses.Richard M. PowellMarlies J. W. PeetersAnne RahbechPia AehnlichTina SeremetPer thor StratenMDPI AGarticleMERTKFLT3CD8<sup>+</sup> T cellsT lymphocytesreceptor tyrosine kinasessmall molecule inhibitorsMedicineRENVaccines, Vol 9, Iss 1294, p 1294 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
MERTK FLT3 CD8<sup>+</sup> T cells T lymphocytes receptor tyrosine kinases small molecule inhibitors Medicine R |
| spellingShingle |
MERTK FLT3 CD8<sup>+</sup> T cells T lymphocytes receptor tyrosine kinases small molecule inhibitors Medicine R Richard M. Powell Marlies J. W. Peeters Anne Rahbech Pia Aehnlich Tina Seremet Per thor Straten Small Molecule Inhibitors of MERTK and FLT3 Induce Cell Cycle Arrest in Human CD8<sup>+</sup> T Cells |
| description |
There is an increasing interest in the development of Receptor Tyrosine Kinases inhibitors (RTKIs) for cancer treatment, as dysregulation of RTK expression can govern oncogenesis. Among the newer generations of RTKIs, many target Mer Tyrosine Kinase (MERTK) and Fms related RTK 3 (FLT3). Next to being overexpressed in many cancers, MERTK and FLT3 have important roles in immune cell development and function. In this study, we address how the new generation and potent RTKIs of MERTK/FLT3 affect human primary CD8<sup>+</sup> T cell function. Using ex vivo T cell receptor (TCR)-activated CD8<sup>+</sup> T cells, we demonstrate that use of dual MERTK/FLT3 inhibitor UNC2025 restricts CD8<sup>+</sup> T proliferation at the G2 phase, at least in part by modulation of mTOR signaling. Cytokine production and activation remain largely unaffected. Finally, we show that activated CD8<sup>+</sup> T cells express FLT3 from day two post activation, and FLT3 inhibition with AC220 (quizartinib) or siRNA-mediated knockdown affects cell cycle kinetics. These results signify that caution is needed when using potent RTKIs in the context of antitumor immune responses. |
| format |
article |
| author |
Richard M. Powell Marlies J. W. Peeters Anne Rahbech Pia Aehnlich Tina Seremet Per thor Straten |
| author_facet |
Richard M. Powell Marlies J. W. Peeters Anne Rahbech Pia Aehnlich Tina Seremet Per thor Straten |
| author_sort |
Richard M. Powell |
| title |
Small Molecule Inhibitors of MERTK and FLT3 Induce Cell Cycle Arrest in Human CD8<sup>+</sup> T Cells |
| title_short |
Small Molecule Inhibitors of MERTK and FLT3 Induce Cell Cycle Arrest in Human CD8<sup>+</sup> T Cells |
| title_full |
Small Molecule Inhibitors of MERTK and FLT3 Induce Cell Cycle Arrest in Human CD8<sup>+</sup> T Cells |
| title_fullStr |
Small Molecule Inhibitors of MERTK and FLT3 Induce Cell Cycle Arrest in Human CD8<sup>+</sup> T Cells |
| title_full_unstemmed |
Small Molecule Inhibitors of MERTK and FLT3 Induce Cell Cycle Arrest in Human CD8<sup>+</sup> T Cells |
| title_sort |
small molecule inhibitors of mertk and flt3 induce cell cycle arrest in human cd8<sup>+</sup> t cells |
| publisher |
MDPI AG |
| publishDate |
2021 |
| url |
https://doaj.org/article/ea4b29a1d4364e7390284cee2fd8917d |
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