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TAM Family Receptor Kinase Inhibition Reverses MDSC-Mediated Suppression and Augments Anti-PD-1 Therapy in Melanoma.
- Source :
-
Cancer immunology research [Cancer Immunol Res] 2019 Oct; Vol. 7 (10), pp. 1672-1686. Date of Electronic Publication: 2019 Aug 26. - Publication Year :
- 2019
-
Abstract
- Myeloid cell receptor tyrosine kinases TYRO3, AXL, and MERTK and their ligands, GAS6 and PROTEIN S, physiologically suppress innate immune responses, including in the tumor microenvironment. Here, we showed that myeloid-derived suppressor cells (MDSC) dramatically upregulated TYRO3, AXL, and MERTK and their ligands [monocytic MDSCs (M-MDSC)>20-fold, polymorphonuclear MDSCs (PMN-MDSC)>15-fold] in tumor-bearing mice. MDSCs from tumor-bearing Mertk <superscript>-/-</superscript> , Axl <superscript>-/-</superscript> , and Tyro3 <superscript>-/-</superscript> mice exhibited diminished suppressive enzymatic capabilities, displayed deficits in T-cell suppression, and migrated poorly to tumor-draining lymph nodes. In coimplantation experiments using TYRO3 <superscript>-/-</superscript> , AXL <superscript>-/-</superscript> , and MERTK <superscript>-/-</superscript> MDSCs, we showed the absence of these RTKs reversed the protumorigenic properties of MDSCs in vivo Consistent with these findings, in vivo pharmacologic TYRO3, AXL, and MERTK inhibition diminished MDSC suppressive capability, slowed tumor growth, increased CD8 <superscript>+</superscript> 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 <superscript>+</superscript> and TYRO3 <superscript>+</superscript> M-MDSCs, PMN-MDSCs, and early-stage MDSCs (e-MDSC) 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.<br /> (©2019 American Association for Cancer Research.)
- Subjects :
- Adolescent
Adult
Aged
Aged, 80 and over
Animals
Cell Line, Tumor
Female
Healthy Volunteers
Humans
Male
Melanoma metabolism
Melanoma pathology
Mice
Mice, Inbred C57BL
Mice, Knockout
Middle Aged
Myeloid-Derived Suppressor Cells drug effects
Myeloid-Derived Suppressor Cells immunology
Tumor Microenvironment
Young Adult
Axl Receptor Tyrosine Kinase
Antineoplastic Agents, Immunological pharmacology
CD8-Positive T-Lymphocytes immunology
Melanoma drug therapy
Myeloid-Derived Suppressor Cells metabolism
Programmed Cell Death 1 Receptor antagonists & inhibitors
Proto-Oncogene Proteins metabolism
Receptor Protein-Tyrosine Kinases metabolism
c-Mer Tyrosine Kinase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2326-6074
- Volume :
- 7
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Cancer immunology research
- Publication Type :
- Academic Journal
- Accession number :
- 31451482
- Full Text :
- https://doi.org/10.1158/2326-6066.CIR-19-0008