EGFR activation disrupts immunotherapy response via SHP2-mediated suppression of tumor-intrinsic response to IFN-γ

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Epidermal growth factor receptor (EGFR)-activating mutations confer resistance to immune checkpoint blockade (ICB) in lung cancer.
• The exact mechanisms driving this resistance and effective therapeutic strategies are not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanisms by which EGFR signaling antagonizes antitumor immune responses.
• To identify therapeutic strategies to overcome ICB resistance in EGFR-driven tumors.

Main Methods:

• Investigated the impact of EGFR overexpression and amplification on ICB response in various cancer models.
• Performed functional studies to assess cellular response to interferon-gamma (IFN-γ) under EGFR activation.
• Utilized mechanistic studies involving SHP2 and STAT1 signaling pathways.
• Evaluated the efficacy of SHP2 inhibition in restoring ICB sensitivity.

Main Results:

• EGFR activation, through overexpression or amplification, impairs cellular response to IFN-γ following ICB treatment.
• This suppression reduces T cell recruitment, antigen presentation, and activation, thereby weakening antitumor immunity.
• EGFR signaling activates SHP2, which accelerates STAT1 dephosphorylation, prematurely terminating the IFN-γ response.
• SHP2 inhibition effectively restored ICB sensitivity in EGFR-activated tumors, reducing tumor burden with a good safety profile.

Conclusions:

• The EGFR/SHP2 axis acts as a critical negative regulator of IFN-γ-mediated antitumor responses during immunotherapy.
• Targeting the SHP2 pathway presents a promising therapeutic strategy to overcome ICB resistance in EGFR-driven cancers, including lung cancer.