The complex role of B7 molecules in tumor immunology

Abstract

T-cell activation requires the interaction of the T-cell receptor with a cognate major histocompatibility complex (MHC)-peptide complex. Initiated by antigen engagement, the adaptive immune response is orchestrated by a complex balance between stimulatory and inhibitory signals that are predominantly controlled by members of the B7 family. Here, we review the current knowledge on B7 family members concerning their constitutive and regulated expression, modulation of the immune response and their role in the evasion of host immune surveillance. We also discuss recent therapeutic strategies that aim to improve immune-cell recognition of tumors and induce tolerance to autoreactive immune responses in normal tissues by manipulating B7 functions.

Figure 1

GO and STOP signals provided by B7 family members in the network of interactions between the tumor–stroma tissue and cytotoxic T lymphocytes (CTLs). (a) Go signals. (i) B7-H1 on activated natural killer (NK) cells binds to an as-yet-unidentified B7-H1 receptor (‘X’) mediating PD-1-independent CTL activation. (ii) Activated antigen-presenting cells (APCs) provide stimulatory signals by binding of B7-1 and B7-2 to CD28 expressed on CTLs, thereby preventing CTL apoptosis and sustaining their activation, proliferation and cytokine secretion. (iii) Furthermore, CTLs are activated by interaction of ICOS with B7-H2 on tumor tissues. (b) STOP signals. The tumor microenvironment provides an immunosuppressive shield by expression of B7-H1, B7-DC (the ligand for both of which is PD-1) and B7-H4, which binds to an as-yet-unidentified receptor (‘Y’) on CTLs. These interactions mediate CTL cell-cycle arrest, repressed cytokine production and entry into apoptosis, resulting in the repression of the anti-tumor attack. CTLs themselves can directly inhibit other CTLs by PD-1–B7-H1 interaction (i). APCs express B7-DC and B7-H1, which bind to PD-1 on CTLs (ii), and both mediate the repression of CTLs. In the presence of IL-10 and IL-6, B7-H4 is expressed on APCs (iii) and tumor-associated macrophages (TAMs) (iv), providing inhibitory signals to CTLs.