双重 Axl/MerTK 抑制剂 INCB081776 可构建促炎肿瘤免疫微环境，并增强头颈癌中抗 PD-L1 的疗效。
Dual Axl/MerTK inhibitor INCB081776 creates a proinflammatory tumor immune microenvironment and enhances anti-PDL1 efficacy in head and neck cancer.
机构信息
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
Rutgers Biomedical Health and Sciences, Rutgers University, Newark, New Jersey, USA.
出版信息
Head Neck. 2023 May;45(5):1255-1271. doi: 10.1002/hed.27340. Epub 2023 Mar 20.
BACKGROUND
The tyrosine kinase receptors Axl and MerTK are highly overexpressed in head and neck cancer (HNC) cells, where they are critical drivers of survival, proliferation, metastasis, and therapeutic resistance.
METHODS
We investigated the role of Axl and MerTK in creating an immunologically "cold" tumor immune microenvironment (TIME) by targeting both receptors simultaneously with a small molecule inhibitor of Axl and MerTK (INCB081776). Effects of INCB081776 and/or anti-PDL1 on mouse oral cancer (MOC) cell growth and on the TIME were evaluated.
RESULTS
Targeting Axl and MerTK can reduce M and induce M macrophage polarization. In vivo, INCB081776 treatment alone or with anti-PDL1 appears to slow MOC tumor growth, increase proinflammatory immune infiltration, and decrease anti-inflammatory immune infiltration.
CONCLUSIONS
This data indicates that simultaneous targeting of Axl and MerTK with INCB081776, either alone or in combination with anti-PDL1, slows tumor growth and creates a proinflammatory TIME in mouse models of HNC.
背景
受体酪氨酸激酶 Axl 和 MerTK 在头颈部癌症（HNC）细胞中高度过表达，它们是这些细胞生存、增殖、转移和治疗抵抗的关键驱动因素。
方法
我们通过使用 Axl 和 MerTK 的小分子抑制剂 INCB081776 同时靶向这两个受体，研究了它们在创建免疫“冷”肿瘤免疫微环境（TIME）中的作用。评估了 INCB081776 和/或抗 PD-L1 对小鼠口腔癌（MOC）细胞生长和 TIME 的影响。
结果
靶向 Axl 和 MerTK 可以减少 M 并诱导 M 巨噬细胞极化。在体内，单独使用 INCB081776 或与抗 PD-L1 联合使用似乎可以减缓 MOC 肿瘤的生长，增加促炎免疫浸润，减少抗炎免疫浸润。
结论
这些数据表明，使用 INCB081776 同时靶向 Axl 和 MerTK，无论是单独使用还是与抗 PD-L1 联合使用，都可以减缓肿瘤生长并在 HNC 的小鼠模型中创建促炎 TIME。
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