Heat shock protein 90 C-terminal inhibitor PNSA promotes anticancer immunology of CD8+T cells

Penisuloxazin A (PNSA), a new compound from the fungus, is a novel C-terminal Hsp90 inhibitor reported by us before. It has been reported to possess antitumor activity and suppresses metastasis of breast cancer cells. However, the influence of PNSA on T cells is not fully understood. Here, we found that PNSA was much less toxic to lymphocytes than to tumor cells and it had no significant effect on populations of CD3+, CD4+ and CD8+ T lymphocytes. We discovered that PNSA directly enhanced the killing capacities of the CD8+ T and CD3+CD25- to CT26 cells, but not that of CD3+ cells due to the increase of Treg cells. What's more, PNSA pretreated tumor cells increase the sensitivity to CD8+ T cells mainly through the degradation of client protein of Hsp90 and declination of PD-L1 expression. Eventually, PNSA enhanced the killing ability of CD8+ and CD3+ T cells by simultaneously acting on lymphocytes and cancer cells. In vivo experiments, PNSA exhibited inhibition effects in the colon adenocarcinoma with increase of CD8 T cell infiltration in tumor tissues. All these results indicate that the novel Hsp90 C-terminal inhibitor-PNSA can promote lytic T cell immunological function to improve anticancer effect of PNSA, which provides a better foundation for anticancer drug development of PNSA in future.

Automated summary

This study found that the new compound PNSA has low toxicity to lymphocytes and does not significantly affect the populations of CD3+, CD4+, and CD8+ T lymphocytes. It directly enhances the killing capacities of CD8+ T and CD3+CD25- cells to CT26 cells, while not affecting CD3+ cells due to the increase of Treg cells. Additionally, PNSA pretreatment of tumor cells increases sensitivity to CD8+ T cells by degrading Hsp90 client proteins and decreasing PD-L1 expression. In in vivo experiments, PNSA inhibits colon adenocarcinoma and increases CD8 T cell infiltration in tumor tissues. These findings suggest that PNSA can improve the immune function of lytic T cells and enhance its anticancer effect, providing a better foundation for the development of PNSA as an anticancer drug in the future.