Polarization of tumor-associated macrophages (TAMs) to classic pro-inflammatory M1 or alternatively activated M2 types plays an important role in establishing tumor microenvironment and determining therapeutic responses. It has become increasingly clear that M2 macrophages contribute to tumor progression by producing anti-inflammatory cytokines and suppressing anti-tumor immunity. AXL receptor tyrosine kinase has recently emerged as a dual therapeutic target in oncology, due to its function in tumor growth, survival and metastasis, as well as immunosuppressive activity. AXL and its ligand Gas6 are both involved in attenuating anti-tumor immune response through modulation of TAM polarization. Thus, targeting the AXL signaling pathway is expected to promote a pro-inflammatory tumor microenvironment, in addition to direct inhibition of tumor growth. SLC-391, a selective small molecule inhibitor for AXL, displays high potency against numerous cancer cell lines through inhibition of AXL/PI3K/AKT-dependent cell proliferation and survival in vitro. Additionally, this compound was also found to alter the cytokine profile expressed in THP1-derived M2 macrophages, including upregulating pro-inflammatory CXCL10 and downregulating anti-inflammatory IL-10. Noticeably, the expression level of AXL was significantly upregulated in THP1-derived macrophages in presence of tumor cell-conditioned medium, which indicated the involvement of AXL in M2 polarization, and therefore strengthening the notion of AXL as a dual therapeutic target. In a co-culture system consisting of THP1-derived macrophages and A549 non-small cell lung cancer cells, SLC-391 targeted AXL activity in both cell types for overall tumor cell suppression through direct and macrophage-mediated inhibition. This observation is supported by inhibition of tumor growth and the increased ratio of M1/M2-polarized TAMs from mice treated with SLC-391 in a CT-26 murine colon carcinoma syngeneic model, considering CT26 cells are not sensitive to SLC-391 in cell-based proliferation assay. In summary, in addition to direct inhibition of tumor cells, SLC-391 also appears to promote anti-tumor immunity through modulation of M2 to M1 transition.

Citation Format: Shenshen Lai, Qin Xu, Jun Yan, Hong Zhang, Zaihui Zhang. AXL inhibitor promotes anti-tumor immunity through modulation of macrophage polarization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3853.