title: B7-H4 expression by nonhematopoietic cells in the tumor microenvironment promotes antitumor immunity.
abstract: The B7 family plays a critical role in both positive and negative regulation of immune responses by engaging a variety of receptors on lymphocytes. Importantly, blocking coinhibitory molecules using antibodies specific for CTLA-4 and PD-1 enhances tumor immunity in a subset of patients. Therefore, it is critical to understand the role of different B7 family members since they may be suitable therapeutic targets. B7-H4 is another member that inhibits T-cell function, and it is also upregulated on a variety of tumors and has been proposed to promote tumor growth. Here, we investigate the role of B7-H4 in tumor development and show that B7-H4 expression inhibits tumor growth in two mouse models. Furthermore, we show that B7-H4 expression is required for antitumor immune responses in a mouse model of mammary tumorigenesis. We found that the expression levels of B7-H4 correlate with MHC class I expression in both mouse and human samples. We show that IFNγ upregulates B7-H4 expression on mouse embryo fibroblasts and that the upregulation of B7-H4 on tumors is dependent on T cells. Notably, patients with breast cancer with increased B7-H4 expression show a prolonged time to recurrence. These studies demonstrate a positive role for B7-H4 in promoting antitumor immunity.
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ramtin
authors.initials: R
authors.lastname: Rahbar
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Albert
authors.initials: A
authors.lastname: Lin
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Magar
authors.initials: M
authors.lastname: Ghazarian
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Helen-Loo
authors.initials: HL
authors.lastname: Yau
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sangeetha
authors.initials: S
authors.lastname: Paramathas
authors.affiliation: Department of Molecular Medicine II, Heinrich Heine University Dösseldorf, Dösseldorf, Germany.
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Lang
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Anita
authors.initials: A
authors.lastname: Schildknecht
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Alisha R
authors.initials: AR
authors.lastname: Elford
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Carlos
authors.initials: C
authors.lastname: Garcia-Batres
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Bernard
authors.initials: B
authors.lastname: Martin
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Laboratory Medicine Program, University Health Network (UHN), Toronto, Ontario, Canada. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Hal K
authors.initials: HK
authors.lastname: Berman
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Wey L
authors.initials: WL
authors.lastname: Leong
authors.affiliation: Department of Surgical Oncology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: David R
authors.initials: DR
authors.lastname: McCready
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Reedijk
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Laboratory Medicine Program, University Health Network (UHN), Toronto, Ontario, Canada. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Done
authors.affiliation: Laboratory Medicine Program, University Health Network (UHN), Toronto, Ontario, Canada. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Naomi
authors.initials: N
authors.lastname: Miller
authors.affiliation: Laboratory Medicine Program, University Health Network (UHN), Toronto, Ontario, Canada. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Bruce
authors.initials: B
authors.lastname: Youngson
authors.affiliation: Immune Regulation Laboratory, Institut de Recherches Cliniques de Montreal (IRCM), Montreal, Quebec, Canada.
authors.forename: Woong-Kyung
authors.initials: WK
authors.lastname: Suh
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Department of Immunology, University of Toronto, Toronto, Ontario, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Department of Immunology, University of Toronto, Toronto, Ontario, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. pohashi@uhnres.utoronto.ca.
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Ohashi
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D053804:Granzymes / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000096:biosynthesis; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology / Q000276:immunology; D059016:Tumor Microenvironment / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*
chemical_list: D014408:Biomarkers, Tumor; D015395:Histocompatibility Antigens Class I; D009363:Neoplasm Proteins; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475826:VTCN1 protein, human; C475824:Vtcn1 protein, mouse; D007371:Interferon-gamma; D053804:Granzymes; C509214:Gzmb protein, mouse