RESUMO
Purpose: It was reported that the EGFR (epidermal growth factor receptor) mutation status was related to primary immune resistance in NSCLC (non-small-cell lung cancer). ICIs (immune checkpoint inhibitors) have poor efficacy and large side effects for people with EGFR mutation. EGFR mutation was considered as a sign of immune therapeutic resistance, but its underlying mechanism is difficult to be determined. Combined with our research basis, we tried to explore the possible mechanism of primary drug resistance in EFGR mutant lung adenocarcinoma through the interaction between the JAK/STAT1 and JAK/STAT3 pathway. Materials and Methods: Cell apoptosis and viability test were used to study the role of the JAK/STAT signalling pathway in lung adenocarcinoma cell survival. Western blot, RT-PCR, and flow cytometry were employed to explore the changes of expression in JAK1/2, STAT1/3, PD-L1, and related signal molecules in the case of activation or inhibition of the JAK/STAT3 signalling pathway. Results: With inhibition of inhibiting the JAK/STAT3 signalling pathway by STAT3 inhibitors, we found IFNγ-JAK-STAT1 pathway activation by IFNγ could further keep lung adenocarcinoma cells from proliferation and promote its apoptosis. The inhibition of the JAK/STAT3 pathway results in the upregulation of JAK1/2, STAT1, IRF1, IRF9, and PD-L1 and downregulation of STAT3 and SOCS1. Conclusions: The absence of the IFNγ-JAK-STAT1 signal pathway is one of the main mechanisms for the ICI endogenous resistance. The abnormal activation of the downstream JAK/STAT3 pathway in cells with EGFR mutation may have antagonistic effects on the STAT1 induced antitumor immune response, which may cause the IFNγ-JAK-STAT1 pathway to lose its function. The mechanism may result in production of the immune tolerance of the EGFR mutant, which promotes immune escape.
