Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, 05505, South Korea.
Department of Biomedical Sciences, Asan Medical Center, AMIST, University of Ulsan, College of Medicine, Seoul, 05505, South Korea.
Biochem Biophys Res Commun. 2023 Nov 5;680:7-14. doi: 10.1016/j.bbrc.2023.09.021. Epub 2023 Sep 11.
AXL is a member of TAM receptor family and has been highlighted as a potential target for cancer treatment. Accumulating evidence has uncovered the critical role of the AXL signaling pathway in tumor growth, metastasis, and resistance against anti-cancer drugs, as well as its association with cancer immune escape. However, the function of AXL as a manipulator of the immune system in the tumor microenvironment (TME) remains unclear. Therefore, in this study, we investigated the impact of AXL on immune cells in the TME of a syngeneic tumor model using AXL knockout (AXL) mice. Compared to AXL wild-type (AXL) mice, tumor growth was significantly suppressed in AXL mice, and an induced population of tumor-infiltrated CD8 T cells and CD103 dendritic cells (DCs) was observed. The change of CD8 T cells and CD103 DCs was also confirmed in tumor-draining lymph nodes (TdLN). In addition, the clonal expansion of OVA-specific CD8 T cells was dominant in AXL mice. Finally, anti-PD-1 treatment evidenced synergistic anti-cancer effects in AXL mice. Overall, our data indicate that AXL signaling may inhibit the clonal expansion of tumor-specific CD8 T cells through the regulation of the migration of CD8 T cells and DCs in TME. Thus, AXL may be a powerful molecular target to improve anti-cancer effects through single or combined therapy with immune checkpoint inhibitors (ICI).
AXL 是 TAM 受体家族的一员，已被强调为癌症治疗的潜在靶点。越来越多的证据揭示了 AXL 信号通路在肿瘤生长、转移和抗癌症药物耐药性中的关键作用，以及它与癌症免疫逃逸的关联。然而，AXL 作为肿瘤微环境（TME）中免疫系统的调节剂的功能尚不清楚。因此，在这项研究中，我们使用 AXL 敲除（AXL）小鼠研究了 AXL 对同种肿瘤模型中 TME 中免疫细胞的影响。与 AXL 野生型（AXL）小鼠相比，AXL 小鼠的肿瘤生长明显受到抑制，并且观察到肿瘤浸润的 CD8 T 细胞和 CD103 树突状细胞（DC）的诱导群体。肿瘤引流淋巴结（TdLN）中也证实了 CD8 T 细胞和 CD103 DC 的变化。此外，AXL 小鼠中 OVA 特异性 CD8 T 细胞的克隆扩增占主导地位。最后，抗 PD-1 治疗在 AXL 小鼠中显示出协同的抗癌作用。总体而言，我们的数据表明，AXL 信号可能通过调节 TME 中 CD8 T 细胞和 DC 的迁移来抑制肿瘤特异性 CD8 T 细胞的克隆扩增。因此，AXL 可能是一种强大的分子靶点，通过与免疫检查点抑制剂（ICI）的单一或联合治疗来提高抗癌效果。
