7.3.4 DC-priming Adjuvant
Ten kinds of TLR proteins (11 transcripts) have been identified in humans.Of these, only TLR2 and TLR3 are expressed in antigen-presenting DCs in humans.TLRs other than TLR3 utilize adapters called MyD88 (Table 6.1), which is closely associated with inflammation.Ligandstimulation of TLR3 or part of TLR4 recruits an adapter called TICAM-1 (also called TRIF).7),8)MyD88 induces inflammatory cytokines (i.e., IL-6, TNF-, IL-10, etc.) using NF-5B as a transcription factor.In addition, MyD88 triggers the production of IL-1O in association with Caspase 1 (inflammasome) activation.MyD88 stimulation by TLR agonists usually induces Th2 polarization and regulatory cells.Notably, TLR stimuli cause side reactions of cytokines in host immune responses secondary to infection.Toxins other than pattern molecules may be involved in the development of inflammation in infections with bacteria or viruses.Finally, bystander activation of DCs occurs with infection, which is attributable to the systemic response of cytokines,IFN-/O, and prostanoids.Similarly, vaccination (although there are individual differences in immune response) appears to make it evident that the vaccine is not effective only by the input of antigen molecules, but they can be effective with antigen plus innate immune activation, such as TLR stimulation.Effective vaccines in this scenario always harbor inflammatory toxicity [12,15,16].
Conventional inflammatory adjuvants are activators of innate immunity as well as inducers of inflammatory mediators; nonetheless, their role in DC-primed immune activation has not been clarified.Both the MyD88 and TICAM-1 pathways sufficiently prime DCs, but their qualitative differences remain unknown.In comparison with the MyD88 pathway, TLR3-TICAM-1 mainly works in antigen presenting DCs, which is of benefit for their specificity, with no need to abstract DC-stimulating activity from the whole molecule of adjuvant [12].As with prophylactic vaccines against infections, antigens and adjuvants are needed for therapeutic vaccines where immune memory is established (Figure 7.3).
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Figure 7.3 Functi ons of pri ming 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.
Source: Seya T, Takeda Y, Takashima K, Yoshida S, Azuma M, Matsumoto M.“Adjuvant Immunotherapy for Cancer: Both Dendritic Cell-priming and Check-point Inhibitor Blockade Are Required for Immunotherapy”.ProceedingsoftheJapanAcademy,SeriesB,PhysicalandBiologicalSciences, 2018, 94(3):153-160.
The quality of adjuvanticity in compounds that complement vaccines, such as alum, has been assessed through their efficacy to induce cytokine responses, which do not always reflect their immune enhancing ability, or in other words their DC priming ability.Multivalent metal ions, not limited to aluminum, induce contact dermatitis, which reflects an adverse effect of metals on human cells.The current adjuvants are good for Ab production, which is partly independent of TLRs, but inappropriate for CTL proliferation.This can raise a question as to why an inflammatory poison is regarded as an adjuvant [12].
Immune adjuvants that prime DCs for robust immune-enhancement are similar to poly I:C but without inducing cytokinemia or toxicity are just now being developed.DC-targeting is achieved by the synthesis of a DNA-dsRNA hybrid molecule that selectively activates TLR3 without activating the mitochondrial antiviral signaling pathway.The design of the molecule is intended to prevent systemic inflammation.TLR3 does not link to MyD88 but does to TICAM-1 in antigen-presenting DCs.Adjuvants that specialize in DC-priming and activate antigen-specific immunity could significantly reduce adverse events in immunotherapy, particularly for patients with cancer [12,17].