B7x is a factor in soil and seed promoting cancer metastasis

Abstract

B7x (B7-H4 or B7S1) is a newly discovered inhibitory member of the B7 family of T cell costimulation. Clinical studies have revealed that B7x is overexpressed in a variety of human cancers and, in many cases, correlates with poor clinical outcome including increased metastasis. Little is known, however, regarding the particular function of B7x in cancer. In addition to cancer cells, B7x is expressed in normal peripheral tissues. As metastatic development requires both capable tumor cells and a receptive secondary site, we asked whether B7x, expressed in tissues distal to the primary tumor or on cancer cells themselves, promotes metastasis.;To study the effects on metastasis of B7x expressed in tissues, such as lung, we utilized B7x knockout (B7x-/-) mice and a B7x-negative pulmonary metastasis model, 4T1. In addition to a significant reduction in mammary tumor mass, B7x-/- mice had significantly fewer lung tumor nodules than did wildtype (wt) mice, both in a primary tumor-induced lung metastasis model and in a tail-vein metastasis model. Furthermore, B7x-/- mice showed significantly enhanced survival and the ability to generate an anti-4T1 memory response. B7x-/- mice had higher general and tumor-specific cytokine responses than wt mice, whose lungs were inundated with immunosuppressive tumor associated neutrophils (TANs). Importantly, these TANs strongly bound B7x-Ig fusion protein and inhibited proliferation of both CD4+ and CD8+ T cells. These results suggest that lung-expressed B7x may enable metastasizing cancer cells to escape local anti-tumor immune responses by promoting an immunosuppressive environment involving innate and adaptive immunity.;Concurrently, to study the effects of B7x expression on cancer cells, we generated tumor cell lines overexpressing B7x and intravenously injected the parent or B7x-expressing cells into wt mice. B7x/CT26 and B7x/MC38 cells induced far more lung tumor nodules than their B7x-negative counterparts, resulting in increased cancer mortality. Mechanistic studies are currently underway but do not appear to involve TANs. In summary, these studies suggest that B7x, whether expressed on cancer cells or in the metastatic site, promotes metastatic growth. B7x is thus a promising target for the development of effective immunotherapy against metastatic cancers.