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 VkMYC 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 VkMYC 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	Camille Guillerey, Lucas Ferrari de Andrade, Slavica Vuckovic, Kim Miles, Shin Foong Ngiow, Michelle C R Yong, Michele W L Teng, Marco Colonna, David S Ritchie, Marta Chesi, Martha Chesi, P Leif Bergsagel, Geoffrey R Hill, Mark J Smyth, Ludovic Martinet
Journal	The Journal of clinical investigation (J Clin Invest) Vol. 125 Issue 5 Pg. 2077-89 (May 2015) ISSN: 1558-8238 [Electronic] United States
PMID	25893601 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antibodies, Monoclonal Antigens, Differentiation, T-Lymphocyte Antineoplastic Agents Boronic Acids CD226 antigen CTLA-4 Antigen Ctla4 protein, mouse Neoplasm Proteins Pdcd1 protein, mouse Pore Forming Cytotoxic Proteins Programmed Cell Death 1 Receptor Pyrazines Receptors, Virus Tumor Necrosis Factor Receptor Superfamily, Member 9 perforin, mouse poliovirus receptor Bortezomib Interferon-gamma Cyclophosphamide
Topics	Animals Antibodies, Monoclonal (therapeutic use) Antigens, Differentiation, T-Lymphocyte (genetics, immunology, physiology) Antineoplastic Agents (therapeutic use) Boronic Acids (therapeutic use) Bortezomib CD8-Positive T-Lymphocytes (immunology) CTLA-4 Antigen (antagonists & inhibitors) Crosses, Genetic Cyclophosphamide (therapeutic use) Disease Progression Genes, myc Genetic Predisposition to Disease Immunologic Surveillance (immunology) Immunotherapy Interferon-gamma (deficiency, genetics, physiology) Killer Cells, Natural (immunology) Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Multiple Myeloma (drug therapy, genetics, immunology) Neoplasm Proteins (deficiency, genetics, immunology, physiology) Neoplasm Transplantation Pore Forming Cytotoxic Proteins (deficiency, genetics, physiology) Programmed Cell Death 1 Receptor (antagonists & inhibitors) Pyrazines (therapeutic use) Receptors, Virus (deficiency, genetics, physiology) Tumor Burden Tumor Necrosis Factor Receptor Superfamily, Member 9 (antagonists & inhibitors, immunology)

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