title: Immunosurveillance and therapy of multiple myeloma are CD226 dependent.
abstract: Multiple myeloma (MM) is an age-dependent hematological malignancy. Evaluation of immune interactions that drive MM relies on in vitro experiments that do not reflect the complex cellular stroma involved in MM pathogenesis. Here we used Vk*MYC transgenic mice, which spontaneously develop MM, and demonstrated that the immune system plays a critical role in the control of MM progression and the response to treatment. We monitored Vk*MYC mice that had been crossed with Cd226 mutant mice over a period of 3 years and found that CD226 limits spontaneous MM development. The CD226-dependent anti-myeloma immune response against transplanted Vk*MYC MM cells was mediated both by NK and CD8+ T cells through perforin and IFN-γ pathways. Moreover, CD226 expression was required for optimal antimyeloma efficacy of cyclophosphamide (CTX) and bortezomib (Btz), which are both standardly used to manage MM in patients. Activation of costimulatory receptor CD137 with mAb (4-1BB) exerted strong antimyeloma activity, while inhibition of coinhibitory receptors PD-1 and CTLA-4 had no effect. Taken together, the results of this study provide in vivo evidence that CD226 is important for MM immunosurveillance and indicate that specific immune components should be targeted for optimal MM treatment efficacy. As progressive immunosuppression associates with MM development, strategies aimed to increase immune functions may have important therapeutic implications in MM.
authors.forename: Camille
authors.initials: C
authors.lastname: Guillerey
authors.forename: Lucas
authors.initials: L
authors.lastname: Ferrari de Andrade
authors.forename: Slavica
authors.initials: S
authors.lastname: Vuckovic
authors.forename: Kim
authors.initials: K
authors.lastname: Miles
authors.forename: Shin Foong
authors.initials: SF
authors.lastname: Ngiow
authors.forename: Michelle C R
authors.initials: MC
authors.lastname: Yong
authors.forename: Michele W L
authors.initials: MW
authors.lastname: Teng
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.forename: David S
authors.initials: DS
authors.lastname: Ritchie
authors.forename: Marta
authors.initials: M
authors.lastname: Chesi
authors.forename: Martha
authors.initials: M
authors.lastname: Chesi
authors.forename: P Leif
authors.initials: PL
authors.lastname: Bergsagel
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Hill
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: Ludovic
authors.initials: L
authors.lastname: Martinet
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001897:Boronic Acids / Q000627:therapeutic use; D000069286:Bortezomib; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors; D003433:Crosses, Genetic; D003520:Cyclophosphamide / Q000627:therapeutic use; D018450:Disease Progression; D016259:Genes, myc; D020022:Genetic Predisposition to Disease; D007157:Immunologic Surveillance / Q000276:immunology*; D007167:Immunotherapy; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D009368:Neoplasm Transplantation; D052899:Pore Forming Cytotoxic Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors; D011719:Pyrazines / Q000627:therapeutic use; D011991:Receptors, Virus / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D047368:Tumor Burden; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000037:antagonists & inhibitors / Q000276:immunology; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D000970:Antineoplastic Agents; D001897:Boronic Acids; D000098862:T Lineage-Specific Activation Antigen 1; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D009363:Neoplasm Proteins; C491383:Pdcd1 protein, mouse; D052899:Pore Forming Cytotoxic Proteins; D061026:Programmed Cell Death 1 Receptor; D011719:Pyrazines; D011991:Receptors, Virus; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; C483886:perforin, mouse; C066100:poliovirus receptor; D000069286:Bortezomib; D007371:Interferon-gamma; D003520:Cyclophosphamide