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Immunotherapy

Targeting an adenosine-mediated “don’t eat me signal” augments anti-lymphoma immunity by anti-CD20 monoclonal antibody

Leukemia volume 34, pages 2708–2721 (2020)Cite this article

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Abstract

A growing body of evidence suggests that macrophage immune checkpoint molecules are potential targets in the era of cancer immunotherapy. Here we showed that extracellular adenosine, an abundant metabolite in the tumor microenvironment, critically impedes the therapeutic efficacy of anti-CD20 monoclonal antibodies (mAbs) against B-cell lymphoma. Using a syngeneic B-cell lymphoma model, we showed that host deficiency of adenosine 2A receptor (A2AR), but not A2BR, remarkably improved lymphoma control by anti-CD20 mAb therapy. Conditional deletion of A2AR in myeloid cells, and to a lesser extent in NK cells, augmented therapeutic efficacy of anti-CD20 mAb. Indeed, adenosine signaling impaired antibody-mediated cellular phagocytosis (ADCP) by macrophages and limited the generation of anti-lymphoma CD8+ T cells. Pharmacological inhibition of A2AR overcame the adenosine-mediated negative regulation of ADCP by rituximab in a xeno-transplanted lymphoma model. Moreover, aberrant overexpression of CD39, an apical ecto-enzyme for adenosine generation, showed a negative impact on prognosis in patients with diffuse large B-cell lymphoma, as well as on preclinical efficacy of rituximab. Together, adenosine acts as a “don’t eat me signal”, and may be a potential target to harness anti-lymphoma immunity.

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Fig. 1: Adenosine limits the therapeutic efficacy of anti-CD20 mAb.
Fig. 2: Adenosine negatively regulates antibody-mediated cellular cytotoxicity by NK cells.
Fig. 3: Adenosine negatively regulates antibody-mediated cellular phagocytosis by macrophages.
Fig. 4: Adenosine negatively regulates anti-lymphoma adaptive immunity elicited by anti-CD20 mAb.
Fig. 5: Therapeutic blockade of adenosine signaling augments efficacies of anti-CD20 mAbs.
Fig. 6: The adenosine-rich lymphoma milieu limits rituximab efficacy.

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Acknowledgements

We thank Brodie Quine, Andreea Zaharia, and Liam Town, for mouse breeding and genotyping; the animal house and flow cytometry facilities at QIMR Berghofer Medical Research Institute; and members of Immunology in Cancer and Infection Laboratory for helpful discussion. KN is supported by the Naito Foundation and NHMRC Project Grant (1159593). MJS is supported by a NH&MRC Senior Principal Research Fellowship (1078671) and Program Grant (1132519). KN and MJS were recipients of a Leukemia Foundation of Australia SERP grant.

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Authors and Affiliations

  1. Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, 4006, QLD, Australia

    Kyohei Nakamura, Mika Casey, Frank Vari & Mark J. Smyth

  2. Mater Research, University of Queensland, Translational Research Institute, University of Queensland, Brisbane, QLD, Australia

    Harald Oey & Maher K. Gandhi

  3. Centre de Recherche du Centre Hospitalier de l’Université de Montréal et Institut du Cancer de Montréal, Montreal, QC, Canada

    John Stagg

  4. Princess Alexandra Hospital, Brisbane, QLD, Australia

    Maher K. Gandhi

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Study conception and design: KN and MJS. Acquisition of data: KN and M.C. Analysis and interpretation of data: KN, MC, FV, HO, MKG, and MJS. Drafting of manuscript: KN and MJS.

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Correspondence to Kyohei Nakamura or Mark J. Smyth.

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MJS has research agreements with Bristol Myers Squibb, and Tizona Therapeutics, and MKG has research agreements with Bristol Myers Squibb and Janssen.

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Nakamura, K., Casey, M., Oey, H. et al. Targeting an adenosine-mediated “don’t eat me signal” augments anti-lymphoma immunity by anti-CD20 monoclonal antibody. Leukemia 34, 2708–2721 (2020). https://doi.org/10.1038/s41375-020-0811-3

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