Blockade of the B7-H1/PD-1 pathway for cancer immunotherapy

Abstract

The aim of cancer immunotherapy is to treat malignant disease by inducing or enhancing cancer specific immune responses. With the identification of tumor-associated antigens (TAAs) in the 1990s, cancer immunotherapy research largely focused on inducing immune responses against TAAs but achieved limited success. More recently, the underlying mechanisms and molecular pathways that cancers manipulate to subvert immune-mediated destruction have been identified, including a set of molecules with potent coinhibitory functions. Coinhibitory molecules are expressed on the surface of immune cells, cancer cells, and stromal cells and negatively regulate immune responses to cancer. In particular, one of these ligand-receptor coinhibitory interactions, B7-H1/PD-1, is critical for modulating immune responses to cancer. This knowledge led to the design of revolutionary new immunotherapeutics based on the manipulation of these molecular pathways. Monoclonal antibodies (mAbs) are the primary immunotherapeutic modality used to promote immune function via antagonism or agonism of inhibitory or stimulatory molecular pathways, respectively. Here, we review current knowledge on the function of the B7-H1/PD-1 pathway in mice and humans, its role in the subversion of immune responses in cancer, and clinical evidence that mAb targeting of this pathway results in profound immune anti-cancer effects.

Keywords: B7-DC; B7-H1; PD-1; cancer; coinhibitory; cosignaling; costimulatory; exhaustion; immunosurveillance; immunotherapy; monoclonal antibody; subversion.

Figure 1

B7-H1/PD-1 mAb blockade reverses T cell suppressor and tumor protective mechanisms. In tumor microenvironments, engagement of PD-1, expressed on CD8+ T cells, with B7-H1, expressed on tumor cells, results in T cell suppression and tumor protection. PD-1 signaling in T cells following engagement of B7-H1 inhibits T cell function resulting in an exhausted phenotype characterized by decreased expression of effector molecules and ultimately may result in T cell deletion. B7-H1 expressed on tumor cells induces anti-apoptotic survival factors in tumor cells following engagement of PD-1 on T cells, while the role of B7-DC in the tumor microenvironment remains unclear at this time. Meanwhile, tumor associated B7-H1 and B7-1 molecules interacting with B7-1 and B7-H1 on T cells, respectively, induce non-functional anergic T cells. Blockade of PD-1 interaction with B7-H1 using anti-PD-1 mAbs can reverse the exhausted phenotype of CD8+ T cells and permits subsequent CD8+ T cells responses against tumor antigens. Blockade of B7-H1 using anti-B7-H1 mAbs reverses CD8+ T cell exhaustion, blocks tumor cell molecular shielding mechanisms and may prevent the inhibitory interactions between B7-H1 and B7-1.