B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells

Abstract

B7-H1 is an immunoglobulin-like immune suppressive molecule broadly detectable on the majority of human and rodent cancers, and its functions have been attributed to delivering an inhibitory signal to its counter-receptor programmed death-1 (PD-1) on T cells. Here we report that B7-H1 on cancer cells receives a signal from PD-1 to rapidly induce resistance against T cell-mediated killing because crippling signaling capacity of B7-H1 but not PD-1 ablates this resistance. Importantly, loss of B7-H1 signaling is accompanied by increased susceptibility to immune-mediated tumoricidal activity. In addition to resistance against T-cell destruction, B7-H1 ؉ cancer cells also become refractory to apoptosis in- IntroductionCancer cells display altered surface molecular signatures that distinguish them quantitatively and qualitatively from their normal derivatives. These modifications in receptor and ligand expression commonly facilitate tumor growth and progression or to evasion of host defense mechanisms. 1,2 For example, some tumor cells down-regulate their cell surface major histocompatibility complex (MHC), which is required for recognition by tumor antigen-specific T lymphocytes. 3 As a result, these tumor cells become less recognizable by the immune system and more resistant to immunemediated destruction. Another example is that during progression, cancer cells frequently overexpress proteases and modify glycosylation of cell surface proteins that are normally involved in tissue repair, remodeling, and homeostasis to facilitate invasion and metastasis. 4,5 In general, these modifications in cell membrane ligands and receptors regulate interactions between tumor cells and nontransformed cells in the microenvironment in a fashion that enhances tumor growth, invasion, and immune resistance.We previously identified an immunoglobulin (Ig)-like molecule termed B7-H1, 6 which is either constitutively or inducibly expressed by the majority of human and rodent cancer cells. 7,8 Ample evidence demonstrates that B7-H1 acts as a ligand for the receptor programmed death-1 (PD-1) to deliver an inhibitory signal to T cells, leading to inhibition of immune responses. 9 The mechanisms underlying B7-H1/PD-1-mediated suppression include induction of apoptosis, anergy, unresponsiveness, and exhaustion of T cells. 7,[10][11][12][13][14] Interaction between B7-H1 and PD-1 is also shown to participate in the suppression of autoimmune diseases and transplantation rejection in animal models. 15-18. A recent study suggests that B7-H1, in addition to PD-1, also binds B7-1 (CD80) on T cells to inhibit their activation. 19 We and others have observed that B7-H1 ϩ tumor cells are much more resistant to CD8 ϩ cytolytic T cell (CTL)-mediated destruction in vitro than their B7-H1-negative parental cells, and this resistance is correlated with decreased efficacy of immunotherapy in mouse tumor models. [20][21][22] Ablation of B7-H1 and PD-1 interaction by neutralizing antibodies could restore CTL-mediated lysis of tumor cells in vitro, suggesting ...

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