TGFb Antagonizes IFNg-Mediated Adaptive Immune Evasion via Activation of the AKT-Smad3-SHP1 Axis in Lung Adenocarcinoma

IFNy-mediated signaling in tumor cells can induce immuno-suppressive responses and cause tumor resistance to immunother-apy. Blocking TGFI3 promotes T lymphocyte infiltration and turns immunologically cold tumors into hot tumors, thereby improving the efficacy of immunotherapy. Several studies have shown that TGFI3 inhibits IFNy signaling in immune cells. We thus sought to determine whether TGFI3 affects IFNy signaling in tumor cells and plays a role in the development of acquired resistance to immu-notherapy. TGFI3 stimulation of tumor cells increased SHP1 phos-phatase activity in an AKT-Smad3-dependent manner, decreased IFNy-mediated tyrosine phosphorylation of JAK1/2 and STAT1, and suppressed the expression of STAT1-dependent immune eva-sion-related molecules, e.g., PD-L1, IDO1, herpes virus entry mediator (HVEM), and galectin-9 (Gal-9). In a lung cancer mouse model, dual blockade of TGFI3 and PD-L1 led to superior antitumor activity and prolonged survival compared with anti-PD-L1 therapy alone. However, prolonged combined treatment resulted in tumor resistance to immunotherapy and increased expression of PD-L1, IDO1, HVEM, and Gal-9. Interestingly, after initial anti-PD-L1 monotherapy, dual TGFI3 and PD-L1 blockade promoted both immune evasion gene expression and tumor growth compared with that in tumors treated with continuous PD-L1 monotherapy. Alternatively, treatment with JAK1/2 inhibitor following initial anti-PD-L1 therapy effectively suppressed tumor growth and downregulated immune evasion gene expression in tumors, indi-cating the involvement of IFNy signaling in immunotherapy resis-tance development. These results demonstrate an unappreciated effect of TGFI3 on the development of IFNy-mediated tumor resistance to immunotherapy.