Dual Axl/MerTK inhibitor INCB081776 creates a proinflammatory tumor immune microenvironment and enhances anti-PDL1 efficacy in head and neck cancer

  • Head Neck. 2023 Mar 20. doi: 10.1002/hed.27340.
Kourtney L Kostecki  1 ,  Mari Iida  1 ,  Anne L Wiley  1 ,  Stanley Kimani  2 ,  Bridget Mehall  1 ,  Kaitlin Tetreault  3 ,  Roxana Alexandridis  3 ,  Menggang Yu  3 ,  Seungpyo Hong  4  5  6 ,  Ravi Salgia  7 ,  Justine Y Bruce  6  8 ,  Raymond B Birge  2 ,  Paul M Harari  1  6 ,  Deric L Wheeler  1  6
Affiliations
  • 1. Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
  • 2. Rutgers Biomedical Health and Sciences, Rutgers University, Newark, New Jersey, USA.
  • 3. Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
  • 4. Pharmaceutical Sciences Division, University of Wisconsin School of Pharmacy, Madison, Wisconsin, USA.
  • 5. Yonsei Frontier Lab and Department of Pharmacy, Yonsei University, Seoul, South Korea.
  • 6. University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA.
  • 7. Department of Medical Oncology and Experimental Therapeutics, Comprehensive Cancer Center, City of Hope, Duarte, California, USA.
  • 8. Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
PMID: 36939040 DOI: 10.1002/hed.27340
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 M2 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.

Keywords
Axl; MerTK; PDL1; head and neck cancer; tumor microenvironment.
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