title: Suppression of Metastases Using a New Lymphocyte Checkpoint Target for Cancer Immunotherapy.
abstract: CD96 has recently been shown as a negative regulator of mouse natural killer (NK)-cell activity, with Cd96(-/-)mice displaying hyperresponsive NK cells upon immune challenge. In this study, we have demonstrated that blocking CD96 with a monoclonal antibody inhibited experimental metastases in three different tumor models. The antimetastatic activity of anti-CD96 was dependent on NK cells, CD226 (DNAM-1), and IFNγ, but independent of activating Fc receptors. Anti-CD96 was more effective in combination with anti-CTLA-4, anti-PD-1, or doxorubicin chemotherapy. Blocking CD96 in Tigit(-/-)mice significantly reduced experimental and spontaneous metastases compared with its activity in wild-type mice. Co-blockade of CD96 and PD-1 potently inhibited lung metastases, with the combination increasing local NK-cell IFNγ production and infiltration. Overall, these data demonstrate that blocking CD96 is a new and complementary immunotherapeutic strategy to reduce tumor metastases.
  
  
  CONCLUSIONS
  This article illustrates the antimetastatic activity and mechanism of action of an anti-CD96 antibody that inhibits the CD96-CD155 interaction and stimulates NK-cell function. Targeting host CD96 is shown to complement surgery and conventional immune checkpoint blockade.
authors.affiliation: Cancer Immunoregulation and Immunotherapy, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Blake
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Kimberley
authors.initials: K
authors.lastname: Stannard
authors.affiliation: Cancer Immunoregulation and Immunotherapy, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Cancer Immunoregulation and Immunotherapy, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Stacey
authors.initials: S
authors.lastname: Allen
authors.affiliation: Cancer Immunoregulation and Immunotherapy, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Michelle C R
authors.initials: MC
authors.lastname: Yong
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Deepak
authors.initials: D
authors.lastname: Mittal
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Amelia Roman
authors.initials: AR
authors.lastname: Aguilera
authors.affiliation: Human Immunity, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. Institute of Infection and Immunity, Cardiff University, Cardiff, United Kingdom.
authors.forename: John J
authors.initials: JJ
authors.lastname: Miles
authors.affiliation: Human Immunity, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Viviana P
authors.initials: VP
authors.lastname: Lutzky
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Lucas Ferrari
authors.initials: LF
authors.lastname: de Andrade
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Martinet
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.affiliation: Division of Cell Biology, Biomedical Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Department for Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Kühnel
authors.affiliation: Department for Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Engin
authors.initials: E
authors.lastname: Gurlevik
authors.affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Bernhardt
authors.affiliation: Cancer Immunoregulation and Immunotherapy, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, The University of Queensland, Herston, Queensland, Australia.
authors.forename: Michele W L
authors.initials: MW
authors.lastname: Teng
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, The University of Queensland, Herston, Queensland, Australia. mark.smyth@qimrberghofer.edu.au.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D007167:Immunotherapy / Q000379:methods; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000556:secondary; D008214:Lymphocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008546:Melanoma, Experimental; D051379:Mice; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000970:Antineoplastic Agents; C116131:CD96 antigen; D060908:CTLA-4 Antigen; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic; C556305:T cell Ig and ITIM domain protein, mouse