Activation of IFN1 signaling by TAK-981 in blood, spleen, or tumor of A20-tumor bearing or B16F10-tumor bearing mice

Intravenous administration of TAK-981 to Balb/c or C57BL/6 mice bearing A20 or B16F10 syngeneic tumors, respectively, resulted in a strong induction of IFN1 pathway genes in peripheral blood leukocytes, spleen and A20 tumor tissues. TAK- 981 dependent upregulation of IFN1 mRNA signature was determined from RNA-Seq data in peripheral blood, spleen and tumor of BALB/c mice bearing A20 tumors. Upregulation of IFN1 ssGSEA scores were calculated in peripheral blood at 4h (P = 0.0011) and 8h (P = 0.0001), in spleen at 4h (P = 0.0002) and 8h (P = 0.0020), and in tumor at 4h (P = 0.0095) and 8h (P = 0.0033) after treatment with the indicated doses of TAK-981. Dose dependent upregulation of IFN1 mRNA signature by TAK-981 was determined from RNA-Seq data in peripheral blood and spleen of C57BL/6 mice bearing B16F10 tumors. Upregulation of IFN1 ssGSEA scores in the blood at 4h (P = 0.001) and 8h (P = 0.0125) and in the spleen at 4h (P = 0.0019) and 8h (P = 0.0796) after treatment with the indicated concentrations of TAK-981. No upregulation of ssGSEA scores was detected in tumors at 4h (P=0.4295) or 8h (P=0.9706) after treatment with TAK-981. P values were calculated by Welch's ANOVA test. Overall design: Blood, spleen and tumor profiles from tissues isolated from Balb/c mice bearing A20 tumors or C57BL/6 mice bearing B16F10 tumors, treated with different doses of TAK-981, 4 or 8 hours after dosing