Cooperative tumor inhibition by CpG-oligodeoxynucleotide and cyclic dinucleotide in head and neck cancer involves T helper cytokine and macrophage phenotype reprogramming

• Published in: Biomedicine & pharmacotherapy 2024-12, Vol.181, p.117692, Article 117692
• Main Authors: Imana, Zaida Nur, Tseng, Jen-Chih, Yang, Jing-Xing, Liu, Yi-Ling, Lin, Po-Yen, Huang, Ming-Hsi, Chen, Linyi, Luo, Yunping, Wang, Chien-Chia, Yu, Guann-Yi, Chuang, Tsung-Hsien
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Cellular Reprogramming - drug effects; CpG-ODN; Cyclic dinucleotide; Cytokines - metabolism; Female; Head and neck cancer; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - immunology; Head and Neck Neoplasms - pathology; Humans; Macrophage; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Mice; Mice, Inbred BALB C; Nucleotides, Cyclic - pharmacology; Oligodeoxyribonucleotides - pharmacology; Phenotype; STING; T-Lymphocytes, Helper-Inducer - drug effects; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Helper-Inducer - metabolism; Th1 Cells - drug effects; Th1 Cells - immunology; TLR9; Toll-Like Receptor 9 - agonists; Toll-Like Receptor 9 - metabolism; Tumor Microenvironment - drug effects
• ISSN: 0753-3322; 1950-6007; 1950-6007
• DOI: 10.1016/j.biopha.2024.117692

Head and neck cancer ranks as the sixth most common cancer worldwide, highlighting the critical need for the development of new therapies to enhance treatment efficacy. The activation of innate immune receptors given their potent immune stimulatory properties aid in the eradication of cancer cells. In this study, we investigated the immune mechanism and anti-tumor function of a Toll-like receptor 9 (TLR9) agonist, CpG-oligodeoxynucleotide-2722 (CpG-2722), in combination with cyclic dinucleotides, which are agonists of stimulator of interferon genes (STING). Our results revealed that CpG-2722 stimulation increased the expression of Th1 pro-inflammatory cytokines. Stimulation by STING agonists exhibited lower expression of Th1 cytokines but higher expression of Th2 cytokines compared to CpG-2722. However, the combination of these two agonists significantly enhanced Th1 cytokines while reducing Th2 cytokines. Moreover, in vivo experiment showed that both CpG-2722 and 2’3’-c-di-AMP suppressed head and neck tumor growth, with their combination proving more effective than the use of these agonists alone. The combined treatment cooperatively promoted the production of Th1 cytokines and type I interferons, while suppressing Th2 cytokines in the tumors as observed in vitro. Additionally, it led to the accumulation of M1 macrophages, dendritic cells, and T cells, shaping a favorable tumor microenvironment for T cell-mediated tumor killing. The anti-tumor activity of the CpG-2722 and 2’3’-c-di-AMP combination depends on the macrophage presence but does not directly activate M1 macrophage polarization, instead working through a reprogrammed cytokine profile. Furthermore, this combination shows a cooperative anti-tumor activity with anti-PD-1 in treating head and neck tumors. Overall, these findings highlight a Th response and macrophage phenotype reprograming involved functional mechanism underlying the cooperative activity of the combination of TLR9 and STING agonists in the immunotherapy of head and neck cancer. [Display omitted] •A combination of CpG-ODN and cyclic dinucleotide cooperatively inhibits tumor.•This combination enhances the efficacy of anti-PD-1 therapy in tumor treatment.•It induces a Th1-dominant, Th2-low polarized immune response in tumor.•The Th1 response leads to M1 macrophage polarization.•The reprogrammed immune responses contribute to enhanced tumor suppression.