Targeting the programmed death-1 pathway in lymphoid neoplasms

Abstract

Programmed death-1 (PD-1) is a co-inhibitory molecule and is seen in CD4+ and CD8+ T cells. Upon binding to its ligands, programmed death ligand-1 (PD-L1) and -2 (PD-L2), PD-1 negatively regulates interleukin 2 (IL-2) production and T cell proliferation. Activated effector T-cells, which kill cancer cells, can be affected by PD-1 signaling in some lymphoid neoplasm that express PD-L1 or PD-L2. PD-L1 expression in tumor cells can be induced by extrinsic signal (i.e. interferon gamma) or intrinsic signals, such as genetic aberrations involving 9p24.1, latent Epstein-Barr virus infection, PD-L1 3'- untranslated region disruptions, and activated Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Anti-PD-1 therapy improves the overall response rate to treatment in patients with lymphoid neoplasms, particularly relapsed/refractory classical Hodgkin lymphoma. Inspired by their success in treating patients with classical Hodgkin lymphoma, medical practitioners have expanded PD-1 therapy, given as a single therapy or in combination with other drugs, to patients with other types of lymphoma. In this review, current clinical trials with anti-PD-1 or anti-PD-L1 drugs are summarized. The results of numerous clinical trials will broaden our understanding of PD-1 pathway and shall expand the list of patients who will get benefit from these agents including those who suffer from lymphoid neoplasms.

Keywords: Immune checkpoint; Lymphoid neoplasms; PD-1; PD-L1; PD-L2.

Figure 1

The two-signal model of T-cell activation. The first signal is a processed antigen presented by the MHC molecule of an APC to TCR of a T cells. This triggers TCR signaling, which is modulated by the antigen-independent co-stimulatory or co-inhibitory signals delivered by APCs. The T cell molecules CD28, PD-1, and CTLA-4 bind to B7-1/B7-2, PD-L1/PD-L2 and B7-1/B7-2, respectively. CD28, when engaged with its ligands, induces cell cycle progression, interleukin-2 production and clonal expansion. In contrast, PD-1 and CTLA-4 induces T cell tolerance when engaged with their respective ligands. APC, antigen-presenting cells; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; MHC, major histocompatibility complex; TCR, T cell receptor; PD-1, programmed death 1; PD-L1/2, programmed death-ligand 1 or 2, +, activation of the pathway; −, inhibition of the pathway.

Figure 2

PD-1 and its downstream effect. Upon binding to ligands, PD-1’s ITIMs and ITSMs are phosphorylated by Src-family tyrosine kinases. The phosphorylated tyrosine residue subsequently recruits SHP-2 and SHP-1/SHP-2 in ITIM and ITSM, respectively. Activated PD-1 eventually hinders PI3K/Akt and RAS/MEK/ERK pathways, thwarts the function of PKC-θ and ZAP70 phosphorylation and inhibits glycolysis. The net effect is decreased cell cycle progression, IL-2 production, T-cell activation and effector T-cell development and increased apoptosis. Src, Src-family tyrosine kinases; ITIM, immunoreceptor tyrosine-based inhibitory motif; ITSM, immunoreceptor tyrosine-based switch motif; P in red circle, phosphorylated tyrosine residues; SHP1 and SHP2, Src homology 2 domain-containing phosphatases, PI3K/Akt, Phosphatidylinositol-4,5-bisphosphate 3-kinase; Akt, Protein kinase B; PKC-θ, protein kinase C-theta; RAS/MEK/ERK, RAS/MEK/ERK pathway.

Figure 3

Images of various lymphoid neoplasms with PD-L1 expression. A–B. Diffuse large B-cell lymphoma, not otherwise specified. Hematoxylin and eosin (A, x400) and PD-L1 stain (B, x400). C–D. Primary mediastinal large B-cell lymphoma. Hematoxylin and eosin (C, x400) and PD-L1 stain (D, x400). E–F. Epstein-Barr virus-positive diffuse large B-cell lymphoma, not otherwise specified. Hematoxylin and eosin (E, x400) and PD-L1 stain (F, x400). G–H. Primary central nervous system lymphoma. Hematoxylin and eosin (G, x400) and PD-L1 stain (H, x400). I–J. Primary testicular lymphoma. Hematoxylin and eosin (I, x400) and PD-L1 stain (J, x400). All PD-L1 stains were performed using SP142 clone (Spring Bioscience, Pleasanton, CA, USA).