title: Newly recruited CD11b+, GR-1+, Ly6C(high) myeloid cells augment tumor-associated immunosuppression immediately following the therapeutic administration of oncolytic reovirus.
abstract: Tumor-associated immunosuppression aids cancer cells to escape immune-mediated attack and subsequent elimination. Recently, however, many oncolytic viruses, including reovirus, have been reported to overturn such immunosuppression and promote the development of a clinically desired antitumor immunity, which is known to promote favorable patient outcomes. Contrary to this existing paradigm, in this article we demonstrate that reovirus augments tumor-associated immunosuppression immediately following its therapeutic administration. Our data show that reovirus induces preferential differentiation of highly suppressive CD11b(+), Gr-1(+), Ly6C(high) myeloid cells from bone marrow hematopoietic progenitor cells. Furthermore, reovirus administration in tumor-bearing hosts drives time-dependent recruitment of CD11b(+), Gr-1(+), Ly6C(high) myeloid cells in the tumor milieu, which is further supported by virus-induced increased expression of numerous immune factors involved in myeloid-derived suppressor cell survival and trafficking. Most importantly, CD11b(+), Gr-1(+), Ly6C(high) myeloid cells specifically potentiate the suppression of T cell proliferation and are associated with the absence of IFN-γ response in the tumor microenvironment early during oncotherapy. Considering that the qualitative traits of a specific antitumor immunity are largely dictated by the immunological events that precede its development, our findings are of critical importance and must be considered while devising complementary interventions aimed at promoting the optimum efficacy of oncolytic virus-based anticancer immunotherapies.
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4R2;
authors.forename: Derek R
authors.initials: DR
authors.lastname: Clements
authors.affiliation: Department of Biology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4R2;
authors.forename: Andra M
authors.initials: AM
authors.lastname: Sterea
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4R2;
authors.forename: Youra
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4R2; and.
authors.forename: Erin
authors.initials: E
authors.lastname: Helson
authors.affiliation: Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4R2; and.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Dean
authors.affiliation: Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4R2; and.
authors.forename: Anna
authors.initials: A
authors.lastname: Nunokawa
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4R2;
authors.forename: Krysta Mila
authors.initials: KM
authors.lastname: Coyle
authors.affiliation: Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4R2; and.
authors.forename: Tanveer
authors.initials: T
authors.lastname: Sharif
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4R2;
authors.forename: Paola
authors.initials: P
authors.lastname: Marcato
authors.affiliation: Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4R2; and Strategy and Organizational Performance, Izaak Walton Killiam Health Centre, Halifax, Nova Scotia, Canada B3K 6R8.
authors.forename: Shashi A
authors.initials: SA
authors.lastname: Gujar
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4R2; Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4R2; and shashi.gujar@dal.ca patrick.lee@dal.ca.
authors.forename: Patrick W K
authors.initials: PW
authors.lastname: Lee
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D002454:Cell Differentiation; D002633:Chemotaxis / Q000276:immunology; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage / Q000276:immunology; D006801:Humans; D056747:Immunomodulation; D012089:Mammalian orthoreovirus 3 / Q000235:genetics / Q000276:immunology; D051379:Mice; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000276:immunology; D010641:Phenotype; D019707:Receptors, Chemokine / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D000950:Antigens, Ly; D039481:CD11b Antigen; C503133:Gr-1 protein, mouse; C494192:Ly-6C antigen, mouse; D019707:Receptors, Chemokine