CD8+ T-cell Responses Are Boosted by Dual PD-1/VEGFR2 Blockade after EGFR Inhibition in Egfr-Mutant Lung Cancer

Area of Science:

• Oncology
• Immunotherapy
• Molecular Biology

Background:

• Epidermal growth factor receptor (EGFR) mutations drive non-small cell lung cancer (NSCLC) in never-smokers.
• EGFR-mutant NSCLC exhibits a non-inflamed tumor microenvironment (TME) with poor CD8+ T-cell infiltration, limiting immune-checkpoint inhibitor efficacy.
• Current immunotherapies show limited benefit in this patient population.

Purpose of the Study:

• To investigate the potential of combining EGFR-tyrosine kinase inhibitors (TKIs) with immune-checkpoint blockade in EGFR-mutant NSCLC.
• To determine the optimal treatment sequence for enhancing anti-tumor CD8+ T-cell responses within the TME.
• To elucidate the mechanisms by which EGFR-TKI influences the TME and immune cell infiltration.

Main Methods:

• Syngeneic EGFR-mutant NSCLC mouse models were utilized.
• Treatment strategies included EGFR-TKI monotherapy, PD-1/VEGFR2 dual blockade, and sequential combinations.
• Flow cytometry and chemokine/chemokine receptor analysis assessed immune cell populations and TME characteristics.

Main Results:

• EGFR-TKI pretreatment induced CD8+ T-cell responses in EGFR-mutant NSCLC tumors.
• Sequential EGFR-TKI followed by PD-1 and VEGFR2 blockade significantly enhanced CD8+ T-cell infiltration and antitumor effects.
• EGFR-TKI increased the CD8+/regulatory T-cell ratio and modulated immunosuppressive factors in the TME.

Conclusions:

• Sequential combination therapy involving EGFR-TKI pretreatment followed by PD-1/VEGFR2 blockade is a promising strategy for EGFR-mutant NSCLC.
• EGFR inhibition is critical for inducing T-cell-mediated anti-tumor immunity in this context.
• Findings may guide the development of novel immunotherapeutic approaches for cancers with driver mutations and non-inflamed TMEs.