Blockade of EGFR improves responsiveness to PD-1 blockade in EGFR-mutated non-small cell lung cancer

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Anti-programmed cell death-1 (PD-1) monoclonal antibody (mAb) efficacy varies in cancers with oncogenic driver mutations.
• Epidermal growth factor receptor (EGFR)-mutated lung adenocarcinomas show limited response to anti-PD-1 mAb therapy.

Purpose of the Study:

• Investigate immunological phenotypes in the tumor microenvironment (TME) of EGFR-mutated lung adenocarcinomas.
• Elucidate the mechanisms underlying anti-PD-1 resistance in this cancer type.
• Evaluate the potential of combining EGFR inhibitors with anti-PD-1 mAb for improved antitumor effects.

Main Methods:

• Analysis of TME immunological phenotypes in EGFR-mutated lung adenocarcinomas.
• Investigation of EGFR signaling pathways (cJun/cJun N-terminal kinase, interferon regulatory factor-1) and their impact on immune cell recruitment (CCL22, CXCL10, CCL5).
• Assessment of erlotinib (EGFR inhibitor) effects on TME and combination therapy with anti-PD-1 mAb in preclinical models.

Main Results:

• EGFR-mutated lung adenocarcinomas exhibit a noninflamed TME with high infiltration of CD4+ effector regulatory T cells.
• EGFR signaling activates cJun/cJun N-terminal kinase, increasing CCL22 and recruiting regulatory T cells, while decreasing interferon regulatory factor-1, reducing CD8+ T cell-attracting chemokines (CXCL10, CCL5).
• Erlotinib reduced CD4+ regulatory T cell infiltration and, combined with anti-PD-1 mAb, demonstrated superior antitumor activity compared to monotherapy.

Conclusions:

• EGFR signaling promotes an immunosuppressive TME in lung adenocarcinoma by recruiting regulatory T cells and hindering cytotoxic T cell infiltration.
• Combining EGFR inhibitors with anti-PD-1 mAb represents a promising strategy to enhance immunotherapy efficacy in EGFR-mutated lung adenocarcinomas.