e23078 Background: Patients with malignant pleural mesothelioma have elevated IL-6 levels in their blood and pleural fluid. IL-6 activates the JAK-STAT pathway and promotes transcriptional activation. Our previous work on a STAT3 inhibitor (BBI-608: napabucasin) as a molecular target drug for malignant pleural mesothelioma confirmed its antitumor effect. In this study, the effect of napabucasin on tumor immunity, specifically on tumor infiltrating lymphocytes, was evaluated. Methods: A mouse-derived malignant pleural mesothelioma cell line (AB22; 1.0 × 105 cells) was subcutaneously injected into BALB/cAJcl mice. When the tumors grew to 250 mm3, the mice were divided into three groups (five mice per group): untreated control, 5 mg/kg napabucasin, and 20 mg/kg napabucasin groups. The drug was orally administered twice daily. Tumor volumes were measured twice weekly, and the subcutaneous tumors were removed 15 days after treatment initiation. Tumor infiltrating lymphocytes were extracted from the tumors, and the CD8+ cell percentage was measured using FACS. Results: The subcutaneous tumors of the mice in the untreated control, 5 mg/kg napabucasin, and 20 mg/kg napabucasin groups grew to 2318 mm3, 1764 mm3, and 1383 mm3, respectively, after 15 days of treatment. Suppression of subcutaneous tumor growth was observed, and the inhibitory effect was greater in the 20 mg/kg than in the 5 mg/kg napabucasin groups. The CD8+ cell percentage of tumor infiltrating lymphocytes for the untreated control, 5 mg/kg napabucasin, and 20 mg/kg napabucasin groups was 8.6%, 6.9%, and 19.0%, respectively. The CD8+ cell percentage increased with the increase in drug dosage. Conclusions: We had previously confirmed the antitumor effect of napabucasin by STAT3 inhibition in malignant pleural mesothelioma. In this study, 20 mg/kg napabucasin increased the CD8+ cell percentage of tumor infiltrating lymphocytes, indicating that the drug appears to enhance tumor immunity and that it may be used in combination with an antitumor immune antibody.
Tumor-infiltrating lymphocytes are functionally inactivated by CD90+ stromal cells and reactivated by combined Ibrutinib and Rapamycin in human pleural mesothelioma
