title: Synergistic effects of host B7-H4 deficiency and gemcitabine treatment on tumor regression and anti-tumor T cell immunity in a mouse model.
abstract: B7-H4 (B7x/B7S1), a B7 family inhibitor of T cell activity, is expressed in multiple human cancers and correlates with decreased infiltrating lymphocytes and poor prognosis. In murine models, tumor-expressed B7-H4 enhances tumor growth and reduces T cell immunity, and blockade of tumor-B7-H4 rescues T cell activity and lowers tumor burden. This implicates B7-H4 as a target for cancer immunotherapy, yet limits the efficacy of B7-H4 blockade exclusively to patients with B7-H4+ tumors. Given the expression of B7-H4 on host immune cells, we have previously shown that BALB/c mice lacking host B7-H4 have enhanced anti-tumor profiles, yet similar 4T1 tumor growth relative to control. Given that T cell-mediated immunotherapies work best for tumors presenting tumor-associated neoantigens, we further investigated the function of host B7-H4 in the growth of a more immunogenic derivative, 4T1-12B, which is known to elicit strong anti-tumor CD8 T cell responses due to expression of a surrogate tumor-specific antigen, firefly luciferase. Notably, B7-H4 knockout hosts not only mounted greater tumor-associated anti-tumor T cell responses, but also displayed reduced tumors. Additionally, B7-H4-deficiency synergized with gemcitabine to further inhibit tumor growth, often leading to tumor eradication and the generation of protective T cell immunity. These findings imply that inhibition of host B7-H4 can enhance anti-tumor T cell immunity in immunogenic cancers, and can be combined with other anti-cancer therapies to further reduce tumor burden regardless of tumor-B7-H4 positivity.
authors.affiliation: Institut de recherches cliniques de Montréal (IRCM), 110 avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada.|Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada.
authors.forename: Joanne
authors.initials: J
authors.lastname: Leung
authors.affiliation: Institut de recherches cliniques de Montréal (IRCM), 110 avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada.|Département de Médecine (Programmes de Biologie Moléculaire), Université de Montréal, Montréal, QC, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: St-Onge
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Institut du Cancer de Montréal, Faculté de Pharmacie, Université de Montréal, Québec, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Stagg
authors.affiliation: Institut de recherches cliniques de Montréal (IRCM), 110 avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada. woong-kyung.suh@ircm.qc.ca.|Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada. woong-kyung.suh@ircm.qc.ca.|Département de Médecine (Programmes de Biologie Moléculaire), Université de Montréal, Montréal, QC, Canada. woong-kyung.suh@ircm.qc.ca.|Département de Médecine, Université de Montréal, Montréal, QC, Canada. woong-kyung.suh@ircm.qc.ca.|Département de Microbiologie, Infectiologie, et Immunologie, Université de Montréal, Montréal, QC, Canada. woong-kyung.suh@ircm.qc.ca.
authors.forename: Woong-Kyung
authors.identifier: http://orcid.org/0000-0002-6420-3283
authors.initials: WK
authors.lastname: Suh
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D019496:Cancer Vaccines / Q000276:immunology*; D048708:Cell Growth Processes; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008213:Lymphocyte Activation; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D047368:Tumor Burden; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1 / Q000235:genetics*; D000093542:Gemcitabine
chemical_list: D019496:Cancer Vaccines; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475824:Vtcn1 protein, mouse; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: B7-H4; Cancer immunotherapy; Immune checkpoint blockade; T cell immunity