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IMMUNOTHERAPY

Inhibition of CD39 unleashes macrophage antibody-dependent cellular phagocytosis against B-cell lymphoma

Leukemia volume 37, pages 379–387 (2023)Cite this article

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Abstract

Redirection of tumor-associated macrophages to eliminate tumor cells holds great promise for overcoming therapeutic resistance to rituximab and other antibody drugs. Here, we determined the expression of ectonucleotidases CD39 and CD73 in diffuse large B-cell lymphoma (DLBCL), and examined the impact of extracellular ATP (eATP) metabolism on macrophage-mediated anti-lymphoma immunity. Immunostaining of tissue microarray samples showed that CD39 (the ecto-enzyme for eATP hydrolysis) was highly expressed in tumors with the non-germinal center B-cell-like (non-GCB) subtype, and to a lesser extent tumors with the GCB subtype. By contrast, the expression of CD73 (the ecto-enzyme for adenosine generation) was undetectable in tumor cells. Pharmacological blockade of CD39 prevented eATP degradation and enhanced engulfment of antibody-coated lymphoma cells by macrophages in a P2X7 receptor-dependent manner, indicating that eATP fueled antibody-dependent cellular phagocytosis (ADCP) activity. Importantly, inhibition of CD39 augmented in vivo anti-lymphoma effects by therapeutic antibodies including rituximab and daratumumab. Furthermore, the addition of a CD39 inhibitor to anti-CD20 and anti-CD47 combination therapy significantly improved survival in a disseminated model of aggressive B-cell lymphoma, supporting the benefit of dual targeting CD39-mediated eATP hydrolysis and CD47-mediated “don’t eat me” signal. Together, preventing eATP degradation may be a potential approach to unleash macrophage-mediated anti-lymphoma immunity.

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Fig. 1: The expression status of CD39 and CD73 ectonucleotidases in DLBCL tissues.
Fig. 2: Inhibition of CD39 alters the phenotype of tumor-associated macrophages.
Fig. 3: Preventing eATP degradation stimulates macrophage antibody-dependent cellular phagocytosis against lymphoma cells.
Fig. 4: Preventing eATP degradation enhances the efficacy of anti-CD20 mAb against B-cell lymphoma in vivo.
Fig. 5: Inhibition of CD39 improves the efficacy of rituximab.
Fig. 6: Addition of CD39 inhibitor improves the efficacy of anti-CD20 and anti-CD47 combination therapy.
Fig. 7: Graphic summary of targeting CD39 to unleash macrophage anti-lymphoma immunity.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Dr Tam Hong Nguyen and Dr Nigel Waterhouse for technical assistance, and Dr Prahlad Raninga for critical reading of this manuscript. We appreciate donation support from Play for a Cure Foundation. This project was supported by grant 2000538 awarded through the 2020 Priority-driven Collaborative Cancer Research Scheme and funded by the Leukaemia Foundation with the support of Cancer Australia. KN is supported by the NHMRC Project Grant (1159593) and Naito Foundation.

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Authors and Affiliations

  1. Cancer Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia

    Mika Casey, Kane Segawa, Bianca Nowlan, Basit Salik, Carol Lee, Clay Winterford, Sally Pearson, Jason Madore, William C. Dougall & Kyohei Nakamura

  2. Mater Research, The University of Queensland, Brisbane, QLD, Australia

    Soi Cheng Law, Muhamamed Bilal Sabdia & Maher K. Gandhi

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Contributions

MC and KN designed experiments and wrote the manuscript; MC, KS, BN, BS, CL, and KN performed experimental work; SCL, MBS, CW, SP, and JM prepared histology samples; SCL, MBS, and MKG analyzed clinical data; MC, JM, WCD, MKG, and KN contributed to data interpretation; KN conceived and supervised the study. All authors read and approved the final version of the manuscript.

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Correspondence to Kyohei Nakamura.

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Casey, M., Segawa, K., Law, S.C. et al. Inhibition of CD39 unleashes macrophage antibody-dependent cellular phagocytosis against B-cell lymphoma. Leukemia 37, 379–387 (2023). https://doi.org/10.1038/s41375-022-01794-9

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