1. Dual Axl/MerTK inhibitor INCB081776 creates a proinflammatory tumor immune microenvironment and enhances anti-PDL1 efficacy in head and neck cancer.
- Author
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Kostecki KL, Iida M, Wiley AL, Kimani S, Mehall B, Tetreault K, Alexandridis R, Yu M, Hong S, Salgia R, Bruce JY, Birge RB, Harari PM, and Wheeler DL
- Subjects
- Animals, Mice, c-Mer Tyrosine Kinase, Cell Line, Tumor, Protein Kinase Inhibitors pharmacology, Tumor Microenvironment, Head and Neck Neoplasms, Proto-Oncogene Proteins
- Abstract
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
2 and induce M1 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., (© 2023 The Authors. Head & Neck published by Wiley Periodicals LLC.)- Published
- 2023
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