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Author Notes:

Address correspondence to: Douglas K. Graham, Aflac Cancer and Blood Disorders Center, 2015 Uppergate Dr, Suite 404, Atlanta, Georgia 30322 Emory University School of Medicine. Phone: 404.785.3874; Email: Douglas.Graham@choa.org.

Or to: Alisa Lee-Sherick, Pediatric Hematology, Oncology & BMT, University of Colorado, School of Medicine, 12800 E 19th Ave, P18-4115, Aurora, Colorado 80045, USA. Phone: 303.724.8236; Email: Alisa.LeeSherick@ucdenver.edu.

ABLS, KMJ, CJH, MGH, REP, LSP, AAH, XW, and DD designed and performed experiments and analyzed data. SVF, HSE, CTJ, and DKG analyzed data.

ABLS, KMJ, CJH, HSE, DD, and DKG wrote the manuscript.

The authors thank the University of Colorado Cancer Center Flow Cytometry Core for technical assistance (P30CA046934), the Children’s Healthcare of Atlanta and Emory University’s Pediatric Flow Cytometry Core, and the University of Colorado Diabetes & Endocrinology Research Center Molecular Biology Core Facility (NIH P30DK57516) for cell line authentication services.

The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

Conflict of interest: SVF and XW are inventors on a patent describing MRX-2843 (WO2013052417). DKG, HSE, SVF, XW, and DDR are stockholders in Meryx Inc.

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Research Funding:

This work was supported by the NIH (5K12HD068372, to ABLS) (R01CA137078, to DKG), the Pablove Foundation, and Federal Funds from the National Cancer Institute NCI Experimental Therapeutics (NExT) program, NIH, contract no. HHSN261200800001E.

Keywords:

  • Cancer immunotherapy
  • Oncology
  • Therapeutics

MERTK inhibition alters the PD-1 axis and promotes anti-leukemia immunity.

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JCI insight

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Volume 3, Number 21

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Abstract:

MERTK is ectopically expressed and promotes survival in acute lymphoblastic leukemia (ALL) cells and is thus a potential therapeutic target. Here we demonstrate both direct therapeutic effects of MERTK inhibition on leukemia cells and induction of anti-leukemia immunity via suppression of the coinhibitory PD-1 axis. A MERTK-selective tyrosine kinase inhibitor, MRX-2843, mediated therapeutic anti-leukemia effects in immunocompromised mice bearing a MERTK-expressing human leukemia xenograft. In addition, inhibition of host MERTK by genetic deletion (Mertk-/- mice) or treatment with MRX-2843 significantly decreased tumor burden and prolonged survival in immune-competent mice inoculated with a MERTK-negative ALL, suggesting immune-mediated therapeutic activity. In this context, MERTK inhibition led to significant decreases in expression of the coinhibitory ligands PD-L1 and PD-L2 on CD11b+ monocytes/macrophages in the leukemia microenvironment. Furthermore, although T cells do not express MERTK, inhibition of MERTK indirectly decreased PD-1 expression on CD4+ and CD8+ T cells and decreased the incidence of splenic FOXP3+ Tregs at sites of leukemic infiltration, leading to increased T cell activation. These data demonstrate direct and immune-mediated therapeutic activities in response to MERTK inhibition in ALL models and provide validation of a translational agent targeting MERTK for modulation of tumor immunity.

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© 2018, American Society for Clinical Investigation

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