TY - JOUR
T1 - Host B7x promotes pulmonary metastasis of breast cancer
AU - Abadi, Yael M.
AU - Jeon, Hyungjun
AU - Ohaegbulam, Kim C.
AU - Scandiuzzi, Lisa
AU - Ghosh, Kaya
AU - Hofmeyer, Kimberly A.
AU - Lee, Jun Sik
AU - Ray, Anjana
AU - Gravekamp, Claudia
AU - Zang, Xingxing
PY - 2013/4/1
Y1 - 2013/4/1
N2 - B7x (B7-H4 or B7S1) is an inhibitorymember 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 tumorbearing 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.
AB - B7x (B7-H4 or B7S1) is an inhibitorymember 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 tumorbearing 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.
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U2 - 10.4049/jimmunol.1202439
DO - 10.4049/jimmunol.1202439
M3 - Article
C2 - 23455497
AN - SCOPUS:84875423818
SN - 0022-1767
VL - 190
SP - 3806
EP - 3814
JO - Journal of Immunology
JF - Journal of Immunology
IS - 7
ER -