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The pivotal role of cytotoxic NK cells in mediating the therapeutic effect of anti-CD47 therapy in mycosis fungoides

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Abstract

CD47 is frequently overexpressed on tumor cells and is an attractive therapeutic target. The mechanism by which anti-CD47 immunotherapy eliminates cutaneous lymphoma has not been explored. We utilized CRISPR/Cas-9 CD47 knock-out, depletion of NK cells, and mice genetically deficient in IFN-γ to elucidate the mechanism of anti-CD47 therapy in a murine model of cutaneous T cell lymphoma (CTCL). CD47 was found to be a crucial factor for tumor progression since CD47 KO CTCL exhibited a delay in tumor growth. The treatment of CD47 WT murine CTCL with anti-CD47 antibodies led to a significant reduction in tumor burden as early as four days after the first treatment and accompanied by an increased percentage of cytotoxic NK cells at the tumor site. The depletion of NK cells resulted in marked attenuation of the anti-tumor effect of anti-CD47. Notably, the treatment of CD47 WT tumors in IFN-γ KO mice with anti-CD47 antibodies was efficient, demonstrating that IFN-γ was not required to mediate anti-CD47 therapy. We were able to potentiate the therapeutic effect of anti-CD47 therapy by IFN-α. That combination resulted in an increased number of cytotoxic CD107a + IFN-γ-NK1.1 cells and intermediate CD62L + NKG2a-NK1.1. Correlative data from a clinical trial (clinicaltrials.gov, NCT02890368) in patients with CTCL utilizing SIRPαFc to block CD47 confirmed our in vivo observations.

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Acknowledgements

We are grateful to Antony Green for excellent assistance with CD47 staining of skin samples from patients with mycosis fungoides. Single-cell RNA sequencing was supported by research funding from the Drs. Martin and Dorothy Spatz Charitable Foundation (OEA).

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Trillium Therapeutics (OEA); Drs. Martin and Dorothy Spatz Charitable Foundation (OEA).

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Authors and Affiliations

  1. Cutaneous Lymphoma Program, Department of Dermatology, University of Pittsburgh, 3708 Fifth Avenue, 5th Floor, Suite 500.68, Pittsburgh, PA, 15213, USA

    Oleg Kruglov & Oleg E. Akilov

  2. Trillium Therapeutics Inc, Mississauga, ON, Canada

    Lisa D. S. Johnson, Robert A. Uger, Mark Wong, Eric L. Sievers & Yaping Shou

  3. Department of Immunology and Microbiology, University of Colorado, Aurora, CO, USA

    Angela Minic & Kimberly Jordan

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  1. Oleg Kruglov
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OEA is a clinical investigator for Trillium Therapeutics and a recipient of a research grant from Trillium Therapeutics. No potential conflicts of interest were disclosed by the other authors.

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Kruglov, O., Johnson, L.D.S., Minic, A. et al. The pivotal role of cytotoxic NK cells in mediating the therapeutic effect of anti-CD47 therapy in mycosis fungoides. Cancer Immunol Immunother 71, 919–932 (2022). https://doi.org/10.1007/s00262-021-03051-x

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