Figure 6.

Inhibition of IDH1^R132H function in vivo results in an enhanced IFNɣ signature response and therapeutic efficacy of PD-1 blockade. (A) Mice bearing dTG-IDH1^R132H tumors were treated with vehicle (n=3) or 10 mg/kg AG-881 (n=3) for 14 days. mRNA from tumor samples was collected and analyzed using the Mouse Immunology v2 panel (Nanostring) for significant changes in gene expression resulting from IDH1^R132H inhibition. (B) The top 5 (out of 136 gene sets) significantly upregulated pathways following AG-881 treatment. (C) CD45⁺ single-cell suspensions derived from the dTG-IDH1^R132H tumors of mice treated as in (A) were analyzed by FC for the expression of HLA-DR and PD-L1. *P<0.05, **p<0.002; Student t-test. (D) Schematic representation of the combined AG-881 and PD-1 blockade treatment protocol and Kaplan-Meier survival curves. Vehicle control and isotype antibody (Veh, IgG; n=8), vehicle and PD-1 blocking antibody (Veh, α-PD-1, n=9), AG-881 and isotype antibody (AG-881, IgG; n=9), AG-881 and PD1 blocking antibody (AG-881, α-PD-1, n=8). *p<0.05; long-rank test. dTG, double transgenic; HLA, human leukocyte antigens; NES, normalized enrichment score; padj, adjusted p values.