Cancer Immunol Res. 2019 Aug 26. pii: canimm.0008.2019. doi: 10.1158/2326-6066.CIR-19-0008. [Epub ahead of print]
TAM Family Receptor kinase inhibition reverses MDSC-mediated suppression and augments anti-PD-1 therapy in melanoma.
Holtzhausen A1, Harris W2, Ubil E2, Hunter DM3, Zhao J4, Zhang Y5, Zhang D5, Liu Q5, Wang X5, Graham DK6, Frye SV5, Earp HS7.
1
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill.
2
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine.
3
Division of Medicinal Chemistry and Natural Products and Department of Medicine and Pharmacology, University of North Carolina at Chapel Hill.
4
Department of Chemistry, Novartis Institute for Biomedical Research at Shanghai.
5
Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina at Chapel Hill.
6
Pediatrics, Aflac Cancer and Blood Disorders Center at Children's Healthcare of Atlanta and Emory University.
7
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill shelton_earp@med.unc.edu.
Myeloid cell receptor tyrosine kinases (RTK) TYRO3, AXL and MERTK and their ligands, Gas 6 and Protein S, physiologically suppress innate immune responses, including in the tumor microenvironment. Here, we showed that myeloid-derived suppressor cells (MDSCs) dramatically upregulated TYRO3, AXL and MERTK and their ligands (M-MDSCs>20-fold, PMN-MDSCs>15-fold) in tumor-bearing mice. MDSCs from tumor bearing Mertk-/-, Axl-/- and Tyro3-/- mice exhibited diminished suppressive enzymatic capabilities, displayed deficits in T cell suppression and migrated poorly to tumor-draining lymph nodes (TDLNs). In co-implantation experiments, using TYRO3-/-, AXL-/- and MERTK-/- MDSCs, we showed the absence of these RTKs reversed the pro-tumorigenic properties of MDSCs in vivo. Consistent with these findings, in vivo pharmacologic TYRO3, AXL and MERTK inhibition diminished MDSCs' suppressive capability, slowed tumor growth, increased CD8+ T cell infiltration and augmented anti-PD-1 checkpoint inhibitor immunotherapy. Mechanistically, MERTK regulated MDSC suppression and differentiation in part through regulation of STAT3 serine phosphorylation and nuclear localization. Analysis of metastatic melanoma patients demonstrated an enrichment of circulating MERTK+ and TYRO3+ M-MDSCs, PMN-MDSCs and e-MDSCs relative to these MDSC populations in healthy controls. These studies demonstrated that TYRO3, AXL and MERTK control MDSC functionality and serve as promising pharmacologic targets for regulating MDSC-mediated immune suppression in cancer patients. |
