Synergistic Anti-Tumor Efficacy Achieved by Reversing Drug Resistance through the Regulation of the Tumor Immune Microenvironment with IL-12 and Osimertinib Combination Therapy

Abstract

Abstract Patients receiving osimertinib treatment typically develop resistance around the 10th month after initiation. The most common resistance mechanism is the C797S mutation. Competitive resistance mechanisms identified in T790M-deficient patients include MET amplification, HER2 amplification, aberrant FGFR signaling, BRAF mutation, abnormal activation of insulin-like growth factor 1 receptor (IGF1R), and downstream signaling pathway activation (RAS/RAF/MEK/ERK and PI3K/AKT/mTOR). In this study, we confirmed that IL-12 increases immune cell infiltration in tumor tissue, reduces the number of immunosuppressive and tumor-promoting MDSCs and their subpopulations, promotes immune cells to release more Granzyme B and tumor-killing factor IFN-γ, decreases tumor cell surface expression of PD-L1, improves the immunosuppressive tumor microenvironment, restores immune surveillance, and enhances cancer cell sensitivity to osimertinib. Simultaneously, the combination of IL-12 with osimertinib exerts synergistic and reversal effects on resistance by inhibiting resistance-related signaling pathways PI3K/AKT/m-TOR and RAF/MEK/MAPK. It may also exert anti-tumor metastasis effects by lowering VEGFR1 levels.