Single cell RNA sequencing reveals the suppressive effect of PPP1R15A inhibitor Sephin1 in antitumor immunity

ABSTRACT: Sephin1 is the selective inhibitor of Protein Phosphatase 1 Regulatory Subunit 15A (PPP1R15A), which is an important factor in the integrated stress response (ISR) of mammalian cells. Sephin1 can promote ISR by inhibiting the dephosphorylation of eIF2α, and preventing neurodegenerative disease occurrence in mice. However, we found that Sephin1 plays a protumorigenic role in mouse tumor models by suppressing the antitumor immune activities, which was highly relevant to the function of PPP1R15A. To fully understand the mechanism of Sephin1 to the antitumor immunity, we designed this experiment to explore the function of PPP1R15A and Sephin1 in the single-cell expression level. To understand effect of injection of Sephin1 to the immune cells in blood and tumor microenvironment in mice, we injected Sephin1 to mice intraperitoneally, and then subcutaneously inoculated with B16F1 cells. Blood before/after the tumor development and tumor tissues were collected and immune cells were isolated for single-cell sequencing and bioinformatics analysis afterwards. We found that in C57BL/6 mice, Sephin1 treatment could lead to higher levels of ISR activity and lower levels of antitumor immune activities. Specifically, Sephin1 treatment caused reductions in several tumor-killing immune cell populations, including CD8+ T cells, NK cells and NKT cells. The expression levels of cytotoxicity-related genes in lymphocytes were altered upon Sephin1 treatment. Additionally, TCR repertoire analysis demonstrated that the clonal expansion of tumor-specific T cells was inhibited by Sephin1, resulting in a compromised antitumor immune response. A special TCR+ macrophage subtype was identified to be significantly depleted upon Sephin1 treatment, implying that this type of macrophage plays a key antitumor role in the tumor microenvironment. The effects of Sephin1 were also verified in in vitro experiments and studies of other tumor cell lines. Taken together, these data suggest that inhibiting PPP1R15A promotes tumorigenesis by inducing adverse immune suppression. PPP1R15A has the potential to be an effective target for tumor therapy. Besides, a macrophage subtype, the TCR+ macrophages, played an important role in the anti-tumor immunity and can also be significantly inhibited by Sephin1.

ORGANISM(S): Mus musculus

PROVIDER: GSE220656 | GEO | 2022/12/14

REPOSITORIES: GEO