Co-inhibition of CD73 and A2AR Adenosine Signaling Improves Anti-tumor Immune Responses.
Preclinical studies targeting the adenosinergic pathway have gained much attention for their clinical potential in overcoming tumor-induced immunosuppression. Here, we have identified that co-blockade of the ectonucleotidase that generates adenosine CD73 and the A2A adenosine receptor (A2AR) that mediates adenosine signaling in leuokocytes, by using compound gene-targeted mice or therapeutics that target these molecules, limits tumor initiation, growth, and metastasis. This tumor control requires effector lymphocytes and interferon-γ, while antibodies targeting CD73 promote an optimal therapeutic response in vivo when engaging activating Fc receptors. In a two-way mixed leukocyte reaction using a fully human anti-CD73, we demonstrated that Fc receptor binding augmented the production of proinflammatory cytokines.
Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD 4006, Australia; School of Medicine, The University of Queensland, Herston, QLD 4006, Australia.
Arabella
A
Young
Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD 4006, Australia; School of Medicine, The University of Queensland, Herston, QLD 4006, Australia.
Shin Foong
SF
Ngiow
Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD 4006, Australia.
Deborah S
DS
Barkauskas
MedImmune, LLC., Gaithersburg, MD 20878, USA.
Erin
E
Sult
MedImmune, LLC., Gaithersburg, MD 20878, USA.
Carl
C
Hay
Cancer Immunoregulation and Immunotherapy, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia.
Stephen J
SJ
Blake
MedImmune, LLC., Gaithersburg, MD 20878, USA.
Qihui
Q
Huang
Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD 4006, Australia; School of Medicine, The University of Queensland, Herston, QLD 4006, Australia; Cancer Immunoregulation and Immunotherapy, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia.
Jing
J
Liu
Division of Cell Biology, Biomedical Research Center, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo 113-8421, Japan.
Kazuyoshi
K
Takeda
School of Medicine, The University of Queensland, Herston, QLD 4006, Australia; Cancer Immunoregulation and Immunotherapy, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia.
Michele W L
MWL
Teng
MedImmune, LLC., Gaithersburg, MD 20878, USA.
Kris
K
Sachsenmeier
Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD 4006, Australia; School of Medicine, The University of Queensland, Herston, QLD 4006, Australia. Electronic address: mark.smyth@qimrberghofer.edu.au.
Mark J
MJ
Smyth
D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors* / Q000276:immunology; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000628:therapy; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D043705:Receptor, Adenosine A2A / Q000276:immunology; D015398:Signal Transduction
D058917:Adenosine A2 Receptor Antagonists; D000911:Antibodies, Monoclonal; D043705:Receptor, Adenosine A2A; D015720:5'-Nucleotidase
CD73; adenosine; combination therapy; immunotherapy; tumor