Son Hye-Youn, Jeong Hwan-Kyu
Department of Breast and Endocrine Surgery, Center for Medical Innovation, Seoul National University Hospital, Seoul, South Korea.
School of Biosystems and Biomedical Sciences, Korea University, Seoul, South Korea.
Front Oncol. 2021 Oct 28;11:756225. doi: 10.3389/fonc.2021.756225. eCollection 2021.
Extensive interest in cancer immunotherapy is reported according to the clinical importance of CTLA-4 and (PD-1/PD-L1) [programmed death (PD) and programmed death-ligand (PD-L1)] in immune checkpoint therapies. AXL is a receptor tyrosine kinase expressed in different types of cancer and in relation to resistance against various anticancer therapeutics due to poor clinical prognosis. AXL and its ligand, i.e., growth arrest-specific 6 (GAS6) proteins, are expressed on many cancer cells, and the GAS6/AXL pathway is reported to promote cancer cell proliferation, survival, migration, invasion, angiogenesis, and immune evasion. AXL is an attractive and novel therapeutic target for impairing tumor progression from immune cell contracts in the tumor microenvironment. The GAS6/AXL pathway is also of interest immunologically because it targets fewer antitumor immune responses. In effect, several targeted therapies are selective and nonselective for AXL, which are in preclinical and clinical development in multiple cancer types. Therefore, this review focuses on the role of the GAS6/AXL signaling pathway in triggering the immunosuppressive tumor microenvironment as immune evasion. This includes regulating its composition and activating T-cell exclusion with the immune-suppressive activity of regulatory T cells, which is related to one of the hallmarks of cancer survival. Finally, this article discusses the GAS6/AXL signaling pathway in the context of several immune responses such as NK cell activation, apoptosis, and tumor-specific immunity, especially PD-1/PDL-1 signaling.
根据细胞毒性T淋巴细胞相关抗原4（CTLA-4）和程序性死亡蛋白1/程序性死亡配体1 [PD-1/PD-L1，程序性死亡（PD）和程序性死亡配体（PD-L1）] 在免疫检查点疗法中的临床重要性，癌症免疫疗法受到广泛关注。AXL是一种受体酪氨酸激酶，在不同类型的癌症中均有表达，且由于临床预后较差，与多种抗癌治疗的耐药性相关。AXL及其配体，即生长停滞特异性蛋白6（GAS6），在许多癌细胞上均有表达，据报道，GAS6/AXL信号通路可促进癌细胞增殖、存活、迁移、侵袭、血管生成和免疫逃逸。AXL是一个有吸引力的新型治疗靶点，可通过干扰肿瘤微环境中的免疫细胞相互作用来抑制肿瘤进展。GAS6/AXL信号通路在免疫学方面也备受关注，因为它针对的抗肿瘤免疫反应较少。实际上，有几种针对AXL的靶向疗法既有选择性的，也有非选择性的，目前正处于多种癌症类型的临床前和临床开发阶段。因此，本综述重点关注GAS6/AXL信号通路在触发免疫抑制性肿瘤微环境以实现免疫逃逸方面的作用。这包括调节其组成，并通过调节性T细胞的免疫抑制活性激活T细胞排除，这与癌症存活的特征之一相关。最后，本文在几种免疫反应的背景下讨论了GAS6/AXL信号通路，如自然杀伤细胞激活、细胞凋亡和肿瘤特异性免疫，尤其是PD-1/PD-L1信号通路。
