title: Adenosine Receptor 2A Blockade Increases the Efficacy of Anti-PD-1 through Enhanced Antitumor T-cell Responses.
abstract: Immunotherapy is rapidly emerging as a cancer treatment with high potential. Recent clinical trials with anti-CTLA-4 and anti-PD-1/PD-L1 antibodies (mAbs) suggest that targeting multiple immunosuppressive pathways may significantly improve patient survival. The generation of adenosine by CD73 also suppresses antitumor immune responses through the activation of A2A receptors on T cells and natural killer (NK) cells. We sought to determine whether blockade of A2A receptors could enhance the efficacy of anti-PD-1 mAb. The expression of CD73 by tumor cells limited the efficacy of anti-PD-1 mAb in two tumor models, and this was alleviated with concomitant treatment with an A2A adenosine receptor antagonist. The blockade of PD-1 enhanced A2A receptor expression on tumor-infiltrating CD8(+) T cells, making them more susceptible to A2A-mediated suppression. Thus, dual blockade of PD-1 and A2A significantly enhanced the expression of IFNγ and Granzyme B by tumor-infiltrating CD8(+) T cells and, accordingly, increased growth inhibition of CD73(+) tumors and survival of mice. The results of our study indicate that CD73 expression may constitute a potential biomarker for the efficacy of anti-PD-1 mAb in patients with cancer and that the efficacy of anti-PD-1 mAb can be significantly enhanced by A2A antagonists. We have therefore revealed a potentially novel biomarker for the efficacy of anti-PD-1 that warrants further investigation in patients. Because our studies used SYN-115, a drug that has already undergone phase IIb testing in Parkinson disease, our findings have immediate translational relevance for patients with cancer.
authors: Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. phil.darcy@petermac.org paula.beavis@petermac.org.
authors: Paul A
authors: PA
authors: Beavis
authors: Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
authors: Nicole
authors: N
authors: Milenkovski
authors: Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
authors: Melissa A
authors: MA
authors: Henderson
authors: Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
authors: Liza B
authors: LB
authors: John
authors: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Faculté de Pharmacie et Institut du Cancer de Montréal, Montréal, Québec, Canada.
authors: Bertrand
authors: B
authors: Allard
authors: Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
authors: Sherene
authors: S
authors: Loi
authors: Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia. Department of Immunology, Monash University, Clayton, Victoria, Australia.
authors: Michael H
authors: MH
authors: Kershaw
authors: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Faculté de Pharmacie et Institut du Cancer de Montréal, Montréal, Québec, Canada.
authors: John
authors: J
authors: Stagg
authors: Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia. Department of Immunology, Monash University, Clayton, Victoria, Australia. phil.darcy@petermac.org paula.beavis@petermac.org.
authors: Phillip K
authors: PK
authors: Darcy
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology*; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D045744:Cell Line, Tumor; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology*; D011743:Pyrimidines / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*
chemical_list: C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D058917:Adenosine A2 Receptor Antagonists; D000911:Antibodies, Monoclonal; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011743:Pyrimidines; D014230:Triazoles; D019830:Adenosine-5'-(N-ethylcarboxamide); D007371:Interferon-gamma