Recently, researchers from Central South University in China and other institutions published a research paper titled "Human papillomavirus-encoded circular RNA circE7 promotes immune evasion in head and neck squamous cell carcinoma" in the journal Nature Communications. The study found that human HPV virus downregulates the expression of the immune checkpoint molecule Galectin-9 by encoding circular RNA, circE7, thereby promoting immune escape in head and neck squamous cell carcinoma (HNSCC). Based on this discovery, a new idea of combining TIM-3 (Galectin-9 receptor on T cells) monoclonal antibody with existing PD-1 monoclonal antibody to improve the immunotherapy effect of head and neck squamous cell carcinoma was proposed.
circE7 is the only HPV-encoded circular RNA (circRNA) identified so far, and it is only encoded by high-risk HPV16, and its biological function is still unclear.
By integrating clinical samples of patients with head and neck squamous cell carcinoma (HNSCC) and combining cell and animal experiments, the research team found that circE7 can downregulate the expression of the LGALS9 gene (encoding Galectin-9 protein), inhibit the function of cytotoxic T cells, and promote tumor immune escape. Further analysis found that Galectin-9 promotes CD8+ T cells to secrete cytotoxic cytokines by competitively binding to TIM-3 on the surface of T cells. Galectin-9 can also bind to PD-1 on the surface of T cells to inhibit T cell apoptosis. CircE7 downregulates Galectin-9, resulting in inhibition of CD8+T function and activity. The specific molecular mechanism by which circE7 downregulates LGALS9 expression is that circE7 binds to and inhibits the phosphorylation and activation of acetyl-CoA carboxylase 1 (ACC1), reduces the level of intracellular acetyl-CoA, and leads to a decrease in the acetylation level of H3K27 in the promoter region of the LGALS9 gene, inhibiting the expression of LGALS9 through epigenetic regulation.
Finally, the research team confirmed through in vivo and in vitro models that the combined use of TIM-3 and PD-1 monoclonal antibodies can significantly improve the immunotherapy effect of HNSCC.
Figure 1. The combination of PD-1 and TIM-3 monoclonal antibodies enhances the efficacy of immunotherapy in HNSCC. (Ge J, et al., 2024)
In general, this study expands our understanding of the role of HPV in the pathogenesis of head and neck squamous cell carcinoma, especially the molecular mechanism of immune escape, and provides new targets and potential treatment options for immunotherapy of head and neck squamous cell carcinoma.
Reference
Ge J, et al. Human papillomavirus-encoded circular RNA circE7 promotes immune evasion in head and neck squamous cell carcinoma. Nature Communications, 2024, 15(1): 8609.