Manganese salts function as potent adjuvants

Abstract

Aluminum-containing adjuvants have been used for nearly 100 years to enhance immune responses in billions of doses of vaccines. To date, only a few adjuvants have been approved for use in humans, among which aluminum-containing adjuvants are the only ones widely used. However, the medical need for potent and safe adjuvants is currently continuously increasing, especially those triggering cellular immune responses for cytotoxic T lymphocyte activation, which are urgently needed for the development of efficient virus and cancer vaccines. Manganese is an essential micronutrient required for diverse biological activities, but its functions in immunity remain undefined. We previously reported that Mn2+ is important in the host defense against cytosolic dsDNA by facilitating cGAS-STING activation and that Mn2+ alone directly activates cGAS independent of dsDNA, leading to an unconventional catalytic synthesis of 2′3′-cGAMP. Herein, we found that Mn2+ strongly promoted immune responses by facilitating antigen uptake, presentation, and germinal center formation via both cGAS-STING and NLRP3 activation. Accordingly, a colloidal manganese salt (Mn jelly, MnJ) was formulated to act not only as an immune potentiator but also as a delivery system to stimulate humoral and cellular immune responses, inducing antibody production and CD4+/CD8+ T-cell proliferation and activation by either intramuscular or intranasal immunization. When administered intranasally, MnJ also worked as a mucosal adjuvant, inducing high levels of secretory IgA. MnJ showed good adjuvant effects for all tested antigens, including T cell-dependent and T cell-independent antigens, such as bacterial capsular polysaccharides, thus indicating that it is a promising adjuvant candidate.

The cGAS-STING Pathway: A Promising Immunotherapy Target

“…Although most studies on tumors and inflammatory diseases have shown that cGAS-STING signal pathway activation could induce the M1 polarization of macrophages, some studies on microbial infections have found that activated cGAS-STING signal pathway could also promote the M2 polarization of macrophages. Related studies found that the highly expressed type I IFN triggered by STING activation mediated the M2 polarization of macrophages, characterized by enhanced expression of regulatory/anti-inflammatory molecules PD-L1 and IL-10 in macrophages ( 113 , 123 ). Similarly, another study found that Mycobacterium tuberculosis DNA could further enhance the activation of the cGAS-STING signal pathway induced by pre-exposed silica to promote the type I IFN-dependent M2 macrophages polarization ( 114 ).…”

“…Before that, we have summarized that Mn2 + could serve as an effective drug to produce anti-tumor immune responses via activating the cGAS-STING signal pathway dependent on dsDNA ( 40 ). Further study found that Mn2 + could directly activate cGAS independent of dsDNA to facilitate the antigen uptake and presentation of APCs, thereby inducing the production of antibody and the proliferation and activation of CD4 + /CD8 + T cells to strengthen humoral and cellular immune responses ( 123 ), indicating that Mn2 + could serve as a promising adjuvant against tumors. Similarly, earlier in this article, we have reviewed that STINGVAX (a STING agonist), as the first designed cancer vaccine containing granulocyte-macrophage colony-stimulating factor (GM-CSF) and CDNs, exerted a significant anti-tumor efficacy in multiple therapeutic models via increasing CD8 + TILs infiltration ( 45 ).…”

Combine and conquer: manganese synergizing anti-TGF-β/PD-L1 bispecific antibody YM101 to overcome immunotherapy resistance in non-inflamed cancers

“…Even in poorly immunogenic tumor models such as B16, STING agonist combined with α-PD-1/PD-L1 therapy significantly prolonged survival of mice, relative to corresponding monotherapies [32]. Bivalent manganese (Mn 2+ ) is identified as a natural STING agonist [33][34][35].…”

Chitosan-Poly(Acrylic Acid) Nanoparticles Loaded with R848 and MnCl2 Inhibit Melanoma via Regulating Macrophage Polarization and Dendritic Cell Maturation

“…24,25 Recently, a new type of nano-Mn compound adjuvant has been developed for activating humoral, cellular, and mucosal immunity, especially the cytotoxic T cell-mediated immune response. 26,27 However, excess exposure to Mn 2+ can cause cognitive impairment. 28 The delivery of Mn 2+ with NPs may help in its controlled release, thereby reducing neurotoxicity.…”