Cancer Immunotherapy: Silencing Intracellular Negative Immune Regulators of Dendritic Cells

Abstract

Dendritic cells (DCs) are capable of activating adaptive immune responses, or inducing immune suppression or tolerance. In the tumor microenvironment, the function of DCs is polarized into immune suppression that attenuates the effect of T cells, promoting differentiation of regulatory T cells and supporting tumor progression. Therefore, blocking negative immune regulators in DCs is considered a strategy of cancer immunotherapy. Antibodies can target molecules on the cell surface, but not intracellular molecules of DCs. The delivery of short-hairpin RNAs (shRNA) and small-interfering RNAs (siRNA) should be a strategy to silence specific intracellular targets in DCs. This review provides an overview of the known negative immune regulators of DCs. Moreover, a combination of shRNA/siRNA and DC vaccines, DNA vaccines in animal models, and clinical trials are also discussed.

Keywords: cancer; dendritic cells (DCs); intracellular negative immune regulator; short-hairpin RNA (shRNA); small-interfering RNA (siRNA).

Figure 1

Intracellular negative immune regulators of dendritic cells (DCs). When immune receptors are triggered, downstream kinases such as Janus kinase (JAK) are activated. JAK then activates the signal transducers and activators of transcription 3 (STAT3). Nuclear translocation of phosphorylated-STAT3 (P-STAT3) activates the transcription of STAT3-targeted genes. Silenced Suppressor of Cytokine Signaling (SOCS) 1 and SOCS3 can interact with JAK and block the phosphorylation of STAT3, inhibiting the transcription of STAT3-mediated cytokines. In addition, the canonical nuclear factor-κB (NF-κB) pathway is also triggered by immune receptors. This signal leads to the phosphorylation of the IκB kinase α (IκBα), which associates with the dimers of p50 and RELA (or c-REL). Proteasomal degradation of phospho-IκBα (P-IκBα) results in the nuclear translocation of canonical NF-κB family members, which activates the transcription of downstream genes. Forkhead box O3 (FOXO3) is a transcription factor that inhibits the transcription of pro-inflammatory cytokines. Besides, cytosolic FOXO3 binds to RELA, and this complex decreases the nuclear translocation of NF-κB. Indoleamine 2,3-doixygenase 1 (IDO1) is an enzyme that degrades tryptophan into kynurenine. IDO-expressing DCs suppress the function of effector T cells and induce the expansion of regulatory T cells. Abbreviation: pattern recognition receptors (PRRS); tumor necrosis factor Receptors (TNFRs).

Figure 2

Combination of siRNA/shRNA and other cancer immunotherapies. The inhibition of the negative immune regulator in DCs results in strong immune activation. When DCs are delivered with plasmid DNA (DNA vaccine)-encoding specific tumor antigens or DCs pulsed with specific antigens, DCs-mediated anti-tumor immunity is significantly enhanced. Moreover, the monoclonal antibodies targeting CTLA-4 and PD-1 might further enhance tumor-specific immune activation.