title: Importance of CD200 expression by tumor or host cells to regulation of immunotherapy in a mouse breast cancer model.
abstract: Cell-surface CD200 expression by mouse EMT6 breast tumor cells increased primary tumor growth and metastasis to the draining lymph nodes (DLN) in normal (WT) BALB/c female recipients, while lack of CD200R1 expression in a CD200R1-/- host negated this effect. Silencing CD200 expression in EMT6siCD200 tumor cells also reduced their ability to grow and metastasize in WT animals. The cellular mechanisms responsible for these effects have not been studied in detail. We report characterization of tumor infiltrating (TILs) and draining lymph node (DLN) cells in WT and CD200-/- BALB/c mice, receiving WT tumor cells, or EMT6 lacking CD200 expression (EMT6siCD200 cells). Our data show an important correlation with augmented CD8+ cytotoxic T cells and resistance to tumor growth in mice lacking exposure (on either host cells or tumor) to the immunoregulatory molecule CD200. Confirmation of the importance of such CD8+ cells came from monitoring tumor growth and characterization of the TILs and DLN cells in WT mice challenged with EMT6 and EMT6siCD200 tumors and treated with CD8 and CD4 depleting antibodies. Finally, we have assessed the mechanisms(s) whereby addition of metformin as an augmenting chemotherapeutic agent in CD200-/- animals given EMT6 tumors and treated with a previously established immunotherapy regime can increase host resistance. Our data support the hypothesis that increased autophagy in the presence of metformin increases CD8+ responses and tumor resistance, an effect attenuated by the autophagy inhibitor verteporfin.
authors.affiliation: University Health Network, Department of Surgery, Transplant Research Division, Toronto, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Curry
authors.affiliation: University Health Network, Department of Surgery, Transplant Research Division, Toronto, Canada.
authors.forename: Ismat
authors.initials: I
authors.lastname: Khatri
authors.affiliation: University Health Network, Department of Surgery, Transplant Research Division, Toronto, Canada.
authors.forename: Olha
authors.initials: O
authors.lastname: Kos
authors.affiliation: University Health Network, Department of Surgery, Transplant Research Division, Toronto, Canada.
authors.forename: Fang
authors.initials: F
authors.lastname: Zhu
authors.affiliation: University Health Network, Department of Surgery, Transplant Research Division, Toronto, Canada.|University of Toronto, Department of Immunology, Toronto, Canada.
authors.forename: Reginald
authors.initials: R
authors.lastname: Gorczynski
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D001343:Autophagy / Q000187:drug effects / Q000276:immunology; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression; D020868:Gene Silencing; D006801:Humans; D007116:Immunization, Passive / Q000379:methods*; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008212:Lymphocyte Depletion / Q000379:methods; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D008321:Mammary Glands, Animal / Q000276:immunology* / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000628:therapy; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D064446:Orexin Receptors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D011166:Porphyrins / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D000077362:Verteporfin
chemical_list: D000912:Antibodies, Neoplasm; D015703:Antigens, CD; C501103:Cd200r1 protein, mouse; D064446:Orexin Receptors; D011166:Porphyrins; D034741:RNA, Small Interfering; D000077362:Verteporfin; D008687:Metformin; C042739:antigens, CD200