Abstract
Simple SummaryOK-432 is a potent immunotherapy agent for several types of cancer, including oral cancer. We previously reported that OK-432 treatment can induce the production of high levels of IFN-γ from peripheral blood mononuclear cells (PBMCs). Moreover, the IFN-γ production from PBMCs by OK-432 is impaired by conditioned media (CM) from oral cancer cells. To determine the inhibitory mechanism of IFN-γ production by CM, the genes involved in IFN-γ production was retrieved by cDNA microarray analysis. We found that CD40 played a key role in IFN-γ production via IL-12 production. Although the expression levels of CD40 were upregulated by OK-432 treatment in PBMCs, CM inhibited OK-432-induced CD40 expression. These findings suggest that uncertain soluble factor(s) in CM may suppress IFN-γ production via the CD40/CD40L–IL-12 axis in PBMCs.(1) Background: OK-432 is a penicillin-killed, lyophilized formulation of a low-toxicity strain (Su) of Streptococcus pyogenes (Group A). It is a potent immunotherapy agent for several types of cancer, including oral cancer. We previously showed that (i) OK-432 treatment induces a high amount of IFN-γ production from peripheral blood mononuclear cells (PBMCs), and (ii) conditioned medium (CM) from oral cancer cells suppresses both the IFN-γ production and cytotoxic activity of PBMCs driven by OK-432. The aim of this study was to determine the inhibitory mechanism of OK-432-induced IFN-γ production from PBMCs by CM. (2) Methods: We performed cDNA microarray analysis, quantitative RT-PCR, and ELISA to reveal the inhibitory mechanism of CM. (3) Results: We found that CD40 plays a key role in IFN-γ production via IL-12 production. Although OK-432 treatment upregulated the expression levels of the IL-12p40, p35, and CD40 genes, CM from oral cancer cells downregulate these genes. The amount of IFN-γ production by OK-432 treatment was decreased by an anti-CD40 neutralizing antibody. (4) Conclusions: Our study suggests that uncertain soluble factor(s) produced from oral cancer cells may inhibit IFN-γ production from PBMCs via suppressing the CD40/CD40L–IL-12 axis.
Highlights
OK-432 (Chugai Pharmaceutical, Tokyo, Japan) is a penicillin-killed, lyophilized formulation of a low-toxicity strain (Su) of Streptococcus pyogenes (Group A)
We previously examined the inhibitory effect of the conditioned medium (CM) from B88, HNt, and TYS cells on IFN-γ production from peripheral blood mononuclear cells (PBMCs) by OK-432 treatment [25]
Gene Ontology (GO) enrichment analysis revealed that inflammation-related GOs, including IL-12p35, IL12p40, and CD40, were enriched in the genes whose expression was downregulated by CM treatment (Figure 1A)
Summary
OK-432 (Chugai Pharmaceutical, Tokyo, Japan) is a penicillin-killed, lyophilized formulation of a low-toxicity strain (Su) of Streptococcus pyogenes (Group A). It is known as a potent immunotherapy agent for several types of cancer, including oral cancer [1,2,3,4,5]. Administration of OK-432 induces cytotoxic T lymphocytes (CTL) and cytotoxic macrophages and activates anti-tumor effecter cells, including lymphokine-activated killer (LAK) cells and natural killer (NK) cells [6]. OK-432 shows an anti-tumor effect against several types of cancer via activation of immune cells [7,8,9,10]. OK432 induces cancer antigen-specific CTL via maturation of antigen-presenting cells [11]
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