Adjuvant immunotherapy for cancer: both dendritic cell-priming and check-point inhibitor blockade are required for immunotherapy

Abstract

The immune system eliminates advanced cancer when treated with programmed cell death protein-1 (PD-1) or its ligand (PD-L1) blockade, but PD-1 therapy is effective in only ∼20% of patients with solid cancer. The PD-1 antibody mainly acts on the effector phase of cytotoxic T lymphocytes (CTLs) in tumors but induces no activation of the priming phase of antigen-presenting dendritic cells (DCs). It is reasonable that both DC-priming and PD-1/L1 blocking are mandatory for efficient CTL-mediated tumor cytolysis. For DC-priming, a therapeutic vaccine containing Toll-like receptor (TLR) agonists, namely a priming adjuvant, is a good candidate; however, a means for DC-targeting by TLR adjuvant therapy remains to be developed. TLR adjuvants usually harbor cytokine toxicity, which is a substantial barrier against drug approval. Here, we discuss the functional properties of current TLR adjuvants for cancer immunotherapy and introduce a TLR3-specific adjuvant (ARNAX) that barely induces cytokinemia in mouse models.

Keywords: PD-1/L1 blockade; TLR3; adjuvant; cancer immunotherapy; polyI:C.

Figure 1.

Functions of priming adjuvants. The priming adjuvant targets DCs in draining lymph nodes and induce IL-12 and type 1 IFN to facilitate Th1 skewing, CD8⁺ T cell proliferation and reinvigoration (upper panel). The priming adjuvant promotes DC cross-presentation of external antigens from patients’ cancer cells to proliferate tumor-specific CTLs (lower panel). DC-priming is triggered independent of inflammation or cytokines induced secondary to adjuvant injection (upper panel). Administration of DC-priming adjuvant also resets the tumor microenvironment, which is indispensable for CTL invigoration and migration to tumors (lower panel). PD-1 in T cells and its ligand PD-L1 on tumor cells control CTL tumoricidal activities, and block excess CTL activation (lower panel). Regulatory T cells (Treg) and damage-associated molecular patterns (DAMPs) may control these CTL reactions toward cancer.

Figure 2.

TLR3-specific DC-priming induced by ARNAX. PolyI:C is a virus dsRNA mimic, and it evokes mitochondrial antiviral signaling-mediated systemic cytokine production all over the body (right panel). Selective activation of TLR3 in DCs is accomplished by GpC DNA-capped short dsRNAs (left panel). These enter human cells just by addition to the medium. Of note, human cells do not take up viral dsRNA with no 5′- or 3′-stretch. TICAM-1 is a TLR3-specific adaptor for the induction of IL-12 and type I IFN. It also cross-present in exogenously added antigens onto MHC class I to cross-primed CD8⁺ T cells (lower inset).