Between Yes and No: B7-H4 and T-cell Activation

This is done by either activating or suppressing T cells via targeting immune checkpoint receptors and their respective ligands such as the CTLA-4 receptor and the ligand PD-L1. Although treatments targeting CTLA-4 and PD-L1 have had significant success in treating cancer a portion of patients do not respond.^1,2,3 This has created a need for alternative immunotherapies targeting different B7 molecules like B7-H4 that may be effective in treating non-responding patients.

First proposed by Lafferty and Cunningham, the hypothesis that T cells require two-signals to sustain activation is the basis for many immunotherapies.⁴ The first signal needed for activation is the binding of MHC I/II molecules present on antigen presenting cells (APCs) to the T cell receptor5. While this activates key signaling pathways like PI3K-Akt-MTORC1, MAPK and NFkB, it is by itself not enough to maintain T cell activation.^6,7,8 Therefore, a second signal coming from the activation of the T cell surface receptor CD28 by the B7 ligands CD80 and CD86 present on APCs is needed.⁹ During sustained activation, T cells begin to express immune checkpoint receptors like CTLA-4 that decreases the immune response by out competing CD28 for CD80 and CD86 depriving the T cell of its much needed second stimulus. Importantly, not all B7 molecules promote activation and can be suppressive. For example, the checkpoint receptor PD-1 when bound to the B7 ligand B7-H1 (PD-L1) blocks T cell proliferation, cytokine secretion and cytotoxic activity.^7,8 Thus, the state of T cell activation is regulated between a balance of activating and suppressive signals from immune checkpoint receptors and B7 ligands.

Discovered in 2003, B7-H4 is a member of the B7 family of co-stimulatory proteins that includes B7.1 (CD80), B7.2 (CD86), B7-H1 (CD274, PD-L1), B7-H2 (ICOS-L), B7-H3 (CD276) and B7-DC (CD273, PD-L2) that suppresses T cell proliferation and cytokine production.^10,11,12 Unlike other B7 proteins, B7-H4 mRNA is widely expressed in many tissues including the brain, heart, kidney, lung, ovary, pancreas and liver.¹⁰ But unlike its mRNA expression, there is very little to no protein expression of B7-H4 in normal tissues.¹³ Importantly, B7-H4 protein expression can be induced during inflammatory conditions with in vitro stimulation of cells with lipopolysaccharides, phytohemagglutinin and IFN-γ all increasing B7-H4 protein expression suggesting B7-H4 may be a valuable biomarker for the tumor microenvirnoment.¹⁰

Interest in B7-H4 as a target for treating cancer is born from the observation that it is overexpressed in both tumor cells and tumor-associated macrophages in a growing list of cancers including renal cell carcinoma.¹³, breast cancer¹⁴, ovarian cancer^15,16 and pancreatic cancer¹⁷ Furthermore, the overexpression of B7-H4 is positively associated with disease progression including cancer stage, number T cells and patient survival18,19. Given that B7-H4 suppresses T cell activation, therapeutically blocking B7-H4 signaling is hypothesized to favorably alter the tumor microenvironment allowing of T-cell targeting of cancer cells.

Taken together, while immunotherapy treatments targeting CTLA-4 and PD-L1 have been successful the fact that some patients that do not respond has created a need for new drug targets. Like PD-L1, B7-H4 is a suppressive B7 ligand that is thought to be hijacked by tumor cells to evade the immune response. Given B7-H4's ability to suppress T cell activation and its correlation for disease progression in a growing list of cancers B7-H4 may be a valuable treatment option for patients who do not respond to current immunotherapy treatments.