Dendritic Cells and Programmed Death-1 Blockade: A Joint Venture to Combat Cancer

Abstract

Two decades of clinical cancer research with dendritic cell (DC)-based vaccination have proved that this type of personalized medicine is safe and has the capacity to improve survival, but monotherapy is unlikely to cure the cancer. Designed to empower the patient's antitumor immunity, huge research efforts are set to improve the efficacy of next-generation DC vaccines and to find synergistic combinations with existing cancer therapies. Immune checkpoint approaches, aiming to breach immune suppression and evasion to reinforce antitumor immunity, have been a revelation in the immunotherapy field. Early success of therapeutic antibodies blocking the programmed death-1 (PD-1) pathway has sparked the development of novel inhibitors and combination therapies. Hence, merging immunoregulatory tumor-specific DC strategies with PD-1-targeted approaches is a promising path to explore. In this review, we focus on the role of PD-1-signaling in DC-mediated antitumor immunity. In the quest of exploiting the full potential of DC therapy, different strategies to leverage DC immunopotency by impeding PD-1-mediated immune regulation are discussed, including the most advanced research on targeted therapeutic antibodies, lessons learned from chemotherapy-induced immune activation, and more recent developments with soluble molecules and gene-silencing techniques. An overview of DC/PD-1 immunotherapy combinations that are currently under preclinical and clinical investigation substantiates the clinical potential of such combination strategies.

Keywords: cancer immunotherapy; combination therapy; dendritic cell; programmed death ligand 1/2; programmed death-1.

Figures

Figure 1

How the PD-1/PD-L signaling axis plays a role in DC-mediated orchestration of innate and adaptive immunity. DCs are renowned for their pivotal role in regulating the immune response through interaction with a variety of immune cells. DC-moderated PD-1 signaling has been demonstrated to prototypically result in an inhibitory crosstalk with effector cells, evidenced by (1) reduced infiltration and activation capacities, decreased pro-inflammatory, and increased inhibitory cytokine release by CD8+ and CD4+ T cells; (2) impaired killing, regulatory and reciprocal DC activation properties of NK cells; and (3) impaired activation, Th1-cytokine secretion, and downstream NK cell activation by iNKT cells. On the opposite, a costimulatory role for particular interactions promoting CD4+ T cell memory has been described as well. In crosstalk with Tregs, PD-1 engagement was shown to mediate their proliferation, regulatory function, and de novo generation, contributing to an immune suppressive environment. The role of PD-1-signaling in DC crosstalk with other emerging PD-1-sensitive effector (γδ T cells) and regulatory cells (MDSC, TAM) remains to be elucidated. Abbreviations: DC, dendritic cell; IFN-γ, interferon-γ; iNKT, invariant NK T cell; MDSC, myeloid-derived suppressor cell; NK, natural killer cell; PD-1, programmed death-1; PD-L1, programmed cell death ligand 1; PD-L2, programmed cell death ligand 2; sPD-1, soluble PD-1; sPD-L1, soluble PD-L1; TAM, tumor-associated macrophage; Treg, regulatory T cell.

Figure 2

Applied strategies to leverage DC immunopotency by interfering PD-1/PD-L signaling. DC and tumor cell PD-L1 and/or PD-L2 expression exerts direct inhibitory effects (−, red arrows) on CD8+ T cells and NK cells, while promoting (+, green arrows) regulatory T cell functions. Current strategies to increase the immunogenicity of DC vaccines by interfering the PD-1/PD-L signaling axis include combined systemic blockade by means of PD-L1-blocking moieties. Chemotherapy triggers different mechanisms that can promote DC vaccine efficacy, including the induction of immunogenic cell death favorable for DC activation. Exploiting the PD-1 pathway, platinum-based chemotherapeutics have been demonstrated to lower PD-L expression on DCs while increasing tumor cell PD-L expression, sensitizing the tumor for systemic blockade approaches. In situ engineering of DC vaccines by silencing PD-L with the small molecule dorsomorphin or RNAi constructs was demonstrated to successfully improve the immunopotency of DC vaccines. Abbreviations: DC, dendritic cell; ICD, immunogenic cell death; NK, natural killer cell; PD-1, programmed death-1; PD-L1, programmed cell death ligand 1; PD-L2, programmed cell death ligand 2; RNAi, RNA interference; sPD-1, soluble PD-1; sPD-L1, soluble PD-L1; Treg, regulatory T cell.