title: Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs.
abstract: OBJECTIVE
  Monoclonal antibodies (mAb) that block programmed death (PD)-1 or cytotoxic T lymphocyte antigen (CTLA-4) receptors have been associated with durable clinical responses against a variety of cancer types and hold great potential as novel cancer therapeutics. Recent evidence suggest that targeted blockade of multiple immunosuppressive pathways can induce synergistic antitumor responses.
  
  
  METHODS
  In this study, we investigated whether targeted blockade of CD73, an ectonucleotidase that catabolizes the hydrolysis of extracellular adenosine monophosphate (AMP) to adenosine, can enhance the antitumor activity of anti-CTLA-4 and anti-PD-1 mAbs against transplanted and chemically induced mouse tumors.
  
  
  RESULTS
  Anti-CD73 mAb significantly enhanced the activity of both anti-CTLA-4 and anti-PD-1 mAbs against MC38-OVA (colon) and RM-1 (prostate) subcutaneous tumors, and established metastatic 4T1.2 breast cancer. Anti-CD73 mAb also significantly enhanced the activity of anti-PD-1 mAb against 3-methylcholanthrene (MCA)-induced fibrosarcomas. Gene-targeted mice revealed that single-agent therapies and combinatorial treatments were dependent on host IFN-γ and CD8(+) T cells, but independent of perforin. Interestingly, anti-CD73 mAb preferentially synergized with anti-PD-1 mAb. We investigated the effect of extracellular adenosine on tumor-infiltrating T cells and showed that activation of A2A adenosine receptor enhances PD-1 expression, but not CTLA-4 expression, on tumor-specific CD8+ T cells and CD4+ Foxp3+ T regulatory cells.
  
  
  CONCLUSIONS
  Taken together, our study revealed that targeted blockade of CD73 can enhance the therapeutic activity of anti-PD-1 and anti-CTLA-4 mAbs and may thus potentiate therapeutic strategies targeting immune checkpoint inhibitors in general.
authors: Authors' Affiliations: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Faculté de Pharmacie et Institut du Cancer de Montréal, Montréal, Québec, Canada; Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria; Immunology in Cancer and Infection Laboratory, Queensland Institute of Medical Research; and School of Medicine, University of Queensland, Herston, Queensland, Australia.
authors: Bertrand
authors: B
authors: Allard
authors: Sandra
authors: S
authors: Pommey
authors: Mark J
authors: MJ
authors: Smyth
authors: John
authors: J
authors: Stagg
mesh_terms: D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008297:Male; 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; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; D061026:Programmed Cell Death 1 Receptor; D043705:Receptor, Adenosine A2A; D007371:Interferon-gamma; D015720:5'-Nucleotidase