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Small molecule inhibitors of mertk and flt3 induce cell cycle arrest in human cd8+ t cells

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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+ T cell function. Using ex vivo T cell receptor (TCR)-activated CD8+ T cells, we demonstrate that use of dual MERTK/FLT3 inhibitor UNC2025 restricts CD8+ 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+ 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.

OriginalsprogEngelsk
Artikelnummer1294
TidsskriftVaccines
Vol/bind9
Udgave nummer11
ISSN1554-8600
DOI
StatusUdgivet - nov. 2021

Bibliografisk note

Funding Information:
Funding: This study was supported by the Danish Council for Independent Research (grant no. DFF-1331-00095B), the Danish Cancer Society (grant no. R72-A4396-13-S2), the Training Network for the Immunotherapy of Cancer funded by the EU (IMMUTRAIN; H2020 grant no. 641549 to M.J.W. Peeters and P. thor Straten), The Danielsen Foundation, Axel Musfeldts fond, Dagmar Marshalls Fond, Else og Mogens Wedell-Wedellsborg Fond, AP Møller Fonden, and Den Bøhmske Fond.

Funding Information:
This study was supported by the Danish Council for Independent Research (grant no. DFF-1331-00095B), the Danish Cancer Society (grant no. R72-A4396-13-S2), the Training Network for the Immunotherapy of Cancer funded by the EU (IMMUTRAIN; H2020 grant no. 641549 to M.J.W. Peeters and P. thor Straten), The Danielsen Foundation, Axel Musfeldts fond, Dagmar Marshalls Fond, Else og Mogens Wedell-Wedellsborg Fond, AP M?ller Fonden, and Den B?hmske Fond.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

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