Abstract
Cancer vaccines consist of a tumor-associated antigen (TAA) and adjuvant. These vaccines induce and activate proliferation of TAA-specific cytotoxic T lymphocytes (CTLs), suppressing tumor growth. The therapeutic efficacy of TAA-specific CTLs depends on the properties of tumor microenvironment. The environments make immunosuppressive by function of regulatory T cells and tumor-associated myeloid cells; thus, regulation of these cells is important for successful cancer immunotherapy. We report here that L-ergothioneine (EGT) with the adjuvant Toll-like receptor 2 (TLR2) ligand modulated suppressive microenvironments to be immune-enhancing. EGT did not augment DC-mediated CTL priming or affect CTL activation in draining lymph node and spleen. However, EGT decreased the immuno-suppressive function of tumor-associated macrophages (TAMs). TLR2 stimulation accompanied with EGT administration downregulated expression of PD-L1, CSF-1R, arginase-1, FAS ligand, and TRAIL in TAMs, reflecting reduction of CTL suppression. An anti-oxidative thiol-thione residue of EGT was essential to dampening CTL suppression. The effect was specific to the thiol-thione residue of EGT because no effect was observed with another anti-oxidant N-acetyl-L-cysteine (NAC). A CTL-suppressive environment made by TLR2 is relieved to be improved by the addition of EGT, which may ameliorate the efficacy of vaccine immunotherapy.
Highlights
Cancer immunotherapy has therapeutic merit as a treatment for progressive cancers
CD8+ T cell depletion studies (Figure 1G) suggested that tumor regression occurring with combination treatment of Pam2CSK4 + OVA + EGT was largely dependent on CD8β+ T cells
We demonstrated that EGT was an anti-oxidant that improved cancer immunotherapy using Toll-like receptor 2 (TLR2)/6 ligand in vivo (Figure 7)
Summary
Cancer immunotherapy has therapeutic merit as a treatment for progressive cancers. Cytotoxic T lymphocytes (CTLs) are a key effector inducing tumor cell lysis. Ergothioneine Regulates TAM Function function is usually impaired in the tumor microenvironment of progressive cancers [1, 2]. This finding suggests that improvement of the environment is indispensable for achieving complete remission in immunotherapy. TLR ligand acts on DCs as an adjuvant of cancer vaccines because it induces maturation and cross presentation of DCs [5]. Our study and others showed that a number of TLR ligands facilitate cancer immunotherapy [9,10,11] mainly to increase CTLs in tumor environment. We show that EGT successfully improves in vivo therapeutic efficacy of TLR2 ligand/TAA via controlling TAM function
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