title: Host b7x promotes pulmonary metastasis of breast cancer.
abstract: B7x (B7-H4 or B7S1) is an inhibitory member of the B7 family of T cell costimulation. It is expressed in low levels in healthy peripheral tissues, such as the lung epithelium, but is overexpressed in a variety of human cancers with negative clinical associations, including metastasis. However, the function of B7x in the context of cancer, whether expressed on cancer cells or on surrounding "host" tissues, has not been elucidated in vivo. We used the 4T1 metastatic breast cancer model and B7x knockout (B7x (-/-)) mice to investigate the effect of host tissue-expressed B7x on cancer. We found that 4T1 cells were B7x negative in vitro and in vivo, and B7x(-/-) mice had significantly fewer lung 4T1 tumor nodules than did wild-type mice. Furthermore, B7x(-/-) mice showed significantly enhanced survival and a memory response to tumor rechallenge. Mechanistic studies revealed that the presence of B7x correlated with reduced general and tumor-specific T cell cytokine responses, as well as with an increased infiltration of immunosuppressive cells, including tumor-associated neutrophils, macrophages, and regulatory T cells, into tumor-bearing lungs. Importantly, tumor-associated neutrophils strongly bound B7x protein and inhibited the proliferation of both CD4 and CD8 T cells. These results suggest that host B7x may enable metastasizing cancer cells to escape local antitumor immune responses through interactions with the innate and adaptive immune systems. Thus, targeting the B7x pathway holds much promise for improving the efficacy of immunotherapy for metastatic cancer.
authors: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors: Yael M
authors: YM
authors: Abadi
authors: Hyungjun
authors: H
authors: Jeon
authors: Kim C
authors: KC
authors: Ohaegbulam
authors: Lisa
authors: L
authors: Scandiuzzi
authors: Kaya
authors: K
authors: Ghosh
authors: Kimberly A
authors: KA
authors: Hofmeyer
authors: Jun Sik
authors: JS
authors: Lee
authors: Anjana
authors: A
authors: Ray
authors: Claudia
authors: C
authors: Gravekamp
authors: Xingxing
authors: X
authors: Zang
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000276:immunology / Q000401:mortality / Q000473:pathology*; D039481:CD11b Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007156:Immunologic Memory; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000556:secondary*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D010641:Phenotype; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism
chemical_list: D000950:Antigens, Ly; D039481:CD11b Antigen; D016207:Cytokines; C480309:Ly6G antigen, mouse; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475824:Vtcn1 protein, mouse