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The Interaction of the IFNγ/JAK/STAT1 and JAK/STAT3 Signalling Pathways in EGFR-Mutated Lung Adenocarcinoma Cells
Yaguang Han1, Yan Zhang1, Ying Tian2
1Department of Oncology, Shijiazhuang People's Hospital, Shijiazhuang 050030, China.
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.
Insights
EGFR mutations in lung cancer cause immune resistance by disrupting the IFNγ-JAK-STAT1 pathway, leading to immune escape. Targeting the JAK/STAT3 pathway may overcome this resistance in EGFR-mutant lung adenocarcinoma.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Epidermal growth factor receptor (EGFR) mutations are linked to primary immune resistance in non-small-cell lung cancer (NSCLC).
- Immune checkpoint inhibitors (ICIs) show limited efficacy and increased side effects in patients with EGFR mutations.
- The precise mechanism underlying EGFR mutation-associated immune resistance remains unclear.
Purpose of the Study:
- To investigate the potential mechanism of primary drug resistance in EGFR-mutant lung adenocarcinoma.
- To explore the interaction between the JAK/STAT1 and JAK/STAT3 pathways in this context.
Main Methods:
- Cell apoptosis and viability assays were used to assess the role of the JAK/STAT signaling pathway in lung adenocarcinoma cell survival.
- Western blot, RT-PCR, and flow cytometry were employed to analyze the expression of JAK1/2, STAT1/3, PD-L1, and related molecules under JAK/STAT3 pathway modulation.
Main Results:
- Inhibition of the JAK/STAT3 pathway, using STAT3 inhibitors, led to IFNγ-JAK-STAT1 pathway activation.
- IFNγ-induced JAK-STAT1 pathway activation inhibited lung adenocarcinoma cell proliferation and promoted apoptosis.
- JAK/STAT3 pathway inhibition upregulated JAK1/2, STAT1, IRF1, IRF9, and PD-L1, while downregulating STAT3 and SOCS1.
Conclusions:
- Absence of the IFNγ-JAK-STAT1 pathway is a key mechanism for intrinsic ICI resistance.
- Aberrant JAK/STAT3 activation in EGFR-mutant cells may counteract STAT1-induced anti-tumor immunity, impairing the IFNγ-JAK-STAT1 pathway.
- This impaired pathway contributes to immune tolerance and immune escape in EGFR-mutant lung adenocarcinoma.
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