title: Antimetastatic effects of blocking PD-1 and the adenosine A2A receptor.
abstract: Adenosine targeting is an attractive new approach to cancer treatment, but no clinical study has yet examined adenosine inhibition in oncology despite the safe clinical profile of adenosine A2A receptor inhibitors (A2ARi) in Parkinson disease. Metastasis is the main cause of cancer-related deaths worldwide, and therefore we have studied experimental and spontaneous mouse models of melanoma and breast cancer metastasis to demonstrate the efficacy and mechanism of a combination of A2ARi in combination with anti-PD-1 monoclonal antibody (mAb). This combination significantly reduces metastatic burden and prolongs the life of mice compared with either monotherapy alone. Importantly, the combination was only effective when the tumor expressed high levels of CD73, suggesting a tumor biomarker that at a minimum could be used to stratify patients that might receive this combination. The mechanism of the combination therapy was critically dependent on NK cells and IFNγ, and to a lesser extent, CD8(+) T cells and the effector molecule, perforin. Overall, these results provide a strong rationale to use A2ARi with anti-PD-1 mAb for the treatment of minimal residual and metastatic disease.
authors.affiliation: Authors' Affiliations: Immunology in Cancer and Infection Laboratory and Cancer Immunoregulation and Immunotherapy Laboratories, QIMR Berghofer Medical Research Institute, Herston; School of Medicine, University of Queensland, Queensland, Australia; and.
authors.forename: Deepak
authors.initials: D
authors.lastname: Mittal
authors.affiliation: Authors' Affiliations: Immunology in Cancer and Infection Laboratory and Cancer Immunoregulation and Immunotherapy Laboratories, QIMR Berghofer Medical Research Institute, Herston; School of Medicine, University of Queensland, Queensland, Australia; and.
authors.forename: Arabella
authors.initials: A
authors.lastname: Young
authors.affiliation: Authors' Affiliations: Immunology in Cancer and Infection Laboratory and Cancer Immunoregulation and Immunotherapy Laboratories, QIMR Berghofer Medical Research Institute, Herston;
authors.forename: Kimberley
authors.initials: K
authors.lastname: Stannard
authors.affiliation: Authors' Affiliations: Immunology in Cancer and Infection Laboratory and Cancer Immunoregulation and Immunotherapy Laboratories, QIMR Berghofer Medical Research Institute, Herston;
authors.forename: Michelle
authors.initials: M
authors.lastname: Yong
authors.affiliation: Authors' Affiliations: Immunology in Cancer and Infection Laboratory and Cancer Immunoregulation and Immunotherapy Laboratories, QIMR Berghofer Medical Research Institute, Herston; School of Medicine, University of Queensland, Queensland, Australia; and.
authors.forename: Michele W L
authors.initials: MW
authors.lastname: Teng
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Faculté de Pharmacie et Institut du Cancer de Montréal, Montréal, Québec, Canada.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Allard
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Faculté de Pharmacie et Institut du Cancer de Montréal, Montréal, Québec, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Stagg
authors.affiliation: Authors' Affiliations: Immunology in Cancer and Infection Laboratory and Cancer Immunoregulation and Immunotherapy Laboratories, QIMR Berghofer Medical Research Institute, Herston; School of Medicine, University of Queensland, Queensland, Australia; and mark.smyth@qimrberghofer.edu.au.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D007694:Killer Cells, Natural / Q000276:immunology; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism / Q000556:secondary; D008546:Melanoma, Experimental; D051379:Mice; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000378:metabolism*
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D061026:Programmed Cell Death 1 Receptor; D043705:Receptor, Adenosine A2A