Nakamura et al. assessed the role of adenosine signaling in dampening anti-CD20 mAb-induced immune responses in B cell lymphoma. Anti-CD20 mAb therapy led to increased tumor control against BL3750 lymphoma in adenosine 2A receptor (A2AR)-, but not A2BR-, deficient C57BL/6 mice. Adenosine signaling decreased antibody-mediated cellular cytotoxicity by NK cells, anti-CD20 mAb-mediated cellular phagocytosis by macrophages, antigen-presenting B7-1+MHC-II+ macrophage infiltration, and anti-lymphoma CD8+ T cell generation. Genetic and pharmacological inhibition of adenosine signaling augmented the efficacy of anti-CD20 mAb.
Contributed by Shishir Pant
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.
Author Info: (1) Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, 4006, QLD, Australia. Kyohei.Nakamura@qimrberghofer.edu.au. (2) Immunology in
Author Info: (1) Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, 4006, QLD, Australia. Kyohei.Nakamura@qimrberghofer.edu.au. (2) Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, 4006, QLD, Australia. (3) Mater Research, University of Queensland, Translational Research Institute, University of Queensland, Brisbane, QLD, Australia. (4) Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, 4006, QLD, Australia. (5) Centre de Recherche du Centre Hospitalier de l'Universite de Montreal et Institut du Cancer de Montreal, Montreal, QC, Canada. (6) Mater Research, University of Queensland, Translational Research Institute, University of Queensland, Brisbane, QLD, Australia. Princess Alexandra Hospital, Brisbane, QLD, Australia. (7) Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, 4006, QLD, Australia. mark.smyth@qimrberghofer.edu.au.
