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. 2023 Jan 16;19(3):981–993. doi: 10.7150/ijbs.79852

Figure 6.

Figure 6

Combination of Gal-9 blockade with ATM inhibition increases T cell infiltration. Average frequency of tumor-infiltrating CD45+ cells (A), total T cells (B), CD8+T cells (C), CD4+ T cells (D), IFN-γ+CD8+ T cells (E) and IFN-γ+CD8+ T cells (F) in CT26 tumors harvested from BALB/c mice treated with isotype control, AZD1390 alone, anti-Gal-9 antibody (RG-1) alone, or their combination (n = 3 mice/group). Flow cytometric analysis was performed on day 14 after inoculation with CT26 tumor cells. Data represent the mean ± SEM. n.s., not significant; *, P < 0.05; **, P < 0.01; ***, P < 0.001. (G) Graphical summary of key findings. ATM inhibition triggers mitochondrial DNA (mtDNA) leakage and activates cGAS/STING/IFNβ innate immune pathway in tumor cells. Secreted IFNβ binds to IFNR1, activates the downstream STAT1 signaling and leads to Gal-9 induction. Gal-9 secreted from tumor cells interacts with TIM3 on T cells and induces T cell death. However, Gal-9 neutralizing antibody prevents Gal-9 from binding to TIM3 to increase T cell survival. Therefore, the combination of ATM inhibition and anti-Gal-9 increases T cell infiltration and induces anti-tumor immunity.