Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future

Abstract

Major progress has been made toward our understanding of the programmed death-1/programmed death ligand-1 (PD-1/PD-L1) pathway (referred to as the PD pathway). mAbs are already being used to block the PD pathway to treat human cancers (anti-PD therapy), especially advanced solid tumors. This therapy is based on principles that were discovered through basic research more than a decade ago, but the great potential of this pathway to treat a broad spectrum of advanced human cancers is just now becoming apparent. In this Review, we will briefly review the history and development of anti-PD therapy, from the original benchwork to the most up-to-date clinical results. We will then focus the discussion on three basic principles that define this unique therapeutic approach and highlight how anti-PD therapy is distinct from other immunotherapeutic approaches, namely tumor site immune modulation, targeting tumor-induced immune defects, and repairing ongoing (rather than generating de novo) tumor immunity. We believe that these fundamental principles set the standard for future immunotherapies and will guide our efforts to develop more efficacious and less toxic immune therapeutics to treat human cancers.

Figure 3. Tumor adaptive resistance model.

After activation in lymphoid organs, tumor-specific Teffs enter the tumor site to become TILs. Upon recognition of tumor antigens, TILs produce IFN-γ, which drives PD-L1 expression in the tumor microenvironment. Tumor antigens are presented by tumor cells, stromal cells, and infiltrating hematopoietic cells, including DCs, macrophages, neutrophils, and B lymphocytes; all of these cells can be induced to express PD-L1. Upon binding to PD-1, PD-L1 delivers a suppressive signal to T cells and an antiapoptotic signal to tumor cells, leading to T cell dysfunction and tumor survival.

Figure 2. Mechanisms of PD pathway–induced immunosuppression in the tumor microenvironment.

Tumor cells and other cells in tumor microenvironment can express high levels of PD-L1, which results in suppressed immunity upon interaction with PD-1. PD-L1–expressing cells use multiple mechanisms to suppress tumor immunity. PD-L1⁺ tumor cells and antigen-presenting cells (APCs) can induce T cell apoptosis, anergy, functional exhaustion, and IL-10 production. They can also mediate DC suppression and induce the differentiation of Tregs. PD-L1 can also act as a molecular shield on tumor cells and protect tumor cells from lysis by cytotoxic T lymphocytes (CTLs). iTreg, induced Treg.

Figure 1. The PD pathway.

The PD pathway has at least 5 interacting molecules. PD-L1 and PD-L2, with different expression patterns, were identified as ligands of PD-1, and the interaction of PD-L1 or PD-L2 with PD-1 may induce T cell suppression. PD-L1 was found to interact with B7-1 (CD80) on activated T cells and inhibit T cell activity. PD-L2 has a second receptor, RGMb; initially, this interaction activates T cells, but it subsequently induces respiratory tolerance. PD-L1 on tumor cells can also act as a receptor, and the signal delivered from PD-1 on T cells can protect tumor cells from cytotoxic lysis.