Powell Richard M, Peeters Marlies J W, Rahbech Anne, Aehnlich Pia, Seremet Tina, Thor Straten Per
National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, University Hospital Herlev, 2730 Herlev, Denmark.
Inflammation and Cancer Group, Department of Immunology and Microbiology, University of Copenhagen, 2200 Copenhagen, Denmark.
Vaccines (Basel). 2021 Nov 8;9(11):1294. doi: 10.3390/vaccines9111294.
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.
由于受体酪氨酸激酶（RTK）表达失调可控制肿瘤发生，因此人们对开发用于癌症治疗的受体酪氨酸激酶抑制剂（RTKI）的兴趣与日俱增。在新一代RTKI中，许多靶向Mer酪氨酸激酶（MERTK）和Fms相关RTK 3（FLT3）。除了在许多癌症中过表达外，MERTK和FLT3在免疫细胞发育和功能中也发挥着重要作用。在本研究中，我们探讨了新一代强效MERTK/FLT3 RTKI如何影响人原代CD8 T细胞功能。使用体外T细胞受体（TCR）激活的CD8 T细胞，我们证明使用双重MERTK/FLT3抑制剂UNC2025至少部分通过调节mTOR信号传导来限制CD8 T细胞在G2期的增殖。细胞因子的产生和激活在很大程度上不受影响。最后，我们表明激活的CD8 T细胞在激活后第二天开始表达FLT3，用AC220（quizartinib）抑制FLT3或通过siRNA介导的敲低会影响细胞周期动力学。这些结果表明，在抗肿瘤免疫反应的背景下使用强效RTKI时需要谨慎。
