Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity

Abstract

Genetic alterations and epigenetic dysregulation in cancer cells create a vast array of neoepitopes potentially recognizable by the immune system. Immune checkpoint blockade has the capacity to enhance and sustain endogenous immunity against non-mutated tumor-associated antigens as well as uniquely mutant antigens, establishing durable tumor control. Recent evidence from preclinical models highlights the pivotal role of the Programmed Death-1 (PD-1) T cell co-receptor and its ligands, B7-H1/PD-L1 and B7-DC/PD-L2, in maintaining an immunosuppressive tumor microenvironment. Encouraging early clinical results using blocking agents against components of the PD-1 pathway have validated its importance as a target for cancer immunotherapy.

Copyright © 2011 Elsevier Ltd. All rights reserved.

Figures

Figure 1

PD-1 and CTLA-4 play distinct roles in regulating T cell immunity. CTLA-4 modulates the early phases of activation of naïve or memory T cells in response to TCR stimulation by MHC-peptide complexes displayed by antigen presenting cells (“signal 1”). In contrast, PD-1 is expressed on antigen-experienced T cells in the periphery, and serves to limit the activity of T cells at the time of an inflammatory response, thereby protecting normal tissues from collateral destruction. DC, dendritic cell.

Figure 2

Anti-PD-1 and anti-B7-H1/PD-L1 antibodies (mAbs) might behave differently owing to their ability to block distinct sets of inhibitory interactions. Anti-PD-1 mAbs can block its binding to both B7-H1/PD-L1 and B7-DC/PD-L2, abrogating an inhibitory PD-1-mediated signal in T cells; however, the inhibitory interaction of B7-H1/PD-L1 with B7.1 on T cells is not affected. Conversely, anti-B7-H1/PD-L1 mAbs can block its interactions with both B7.1 and PD-1, but will not block the inhibitory interaction of B7-DC/PD-L2 with PD-1. Both anti-PD-1 and anti-B7-H1/PD-L1 mAbs could potentially block transmission of a retrograde pro-survival signal through B7-H1/PD-L1 into tumor cells [43]. APC, antigen presenting cell.