A dual-function epidermal growth factor receptor pathway substrate 8 (Eps8)-derived peptide exhibits a potent...

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Tumor-associated antigens (TAAs) are crucial for developing T-cell based cancer immunotherapies.
• The epidermal growth factor receptor (EGFR) pathway substrate 8 gene (Eps8) is implicated in cancer progression and a potential TAA.
• Identifying specific T-cell epitopes is vital for effective cancer immunotherapy.

Purpose of the Study:

• To identify novel human leukocyte antigen (HLA)-A*2402-restricted epitopes from the Eps8 protein.
• To evaluate the immunogenicity and antitumor efficacy of these Eps8-derived peptides.
• To investigate the mechanism of action of peptide 327, particularly its effect on EGFR signaling.

Main Methods:

• Utilized an HLA-binding prediction algorithm to identify potential HLA-A*2402-restricted epitopes from Eps8.
• Assessed peptide-specific cytotoxic T lymphocyte (CTL) responses, including cytokine secretion (IFN-γ, IL-2, TNF-α) and cytotoxic activity.
• Evaluated the in vivo antitumor efficacy of peptide-sensitized peripheral blood mononuclear cells (PBMCs) in xenograft models.
• Investigated the effect of peptide 327 on Eps8/EGFR complex formation, EGFR signaling pathway, and cancer cell viability.
• Examined the antitumor activity of peptide 327 conjugated to the TAT sequence (TAT-327).

Main Results:

• Identified three novel HLA-A*2402-restricted epitopes: peptides 327, 534, and 755.
• Peptides 327, 534, and 755 induced peptide-specific CTLs with enhanced IFN-γ secretion and cytotoxic activity against cancer cells.
• Peptide-specific CTLs demonstrated effective antitumor responses, including upregulation of key cytokines and cytotoxic molecules (granzyme B, perforin).
• Treatment with peptide-sensitized PBMCs significantly reduced tumor growth in vivo.
• Peptide 327 disrupted Eps8/EGFR complex formation, suppressed cancer cell viability, blocked EGFR signaling, and reduced downstream target expression.
• TAT-327 exhibited potent antitumor activity and selective cancer cell membrane insertion.
• Peptide 327 and TAT-327 showed anticancer properties in xenograft models.

Conclusions:

• Peptides 327, 534, and 755 are novel HLA-A*2402-restricted epitopes derived from Eps8.
• These peptides can elicit robust peptide-specific CTL responses with significant antitumor activity.
• Peptide 327, by inhibiting Eps8/EGFR interaction, acts as a peptide inhibitor, offering a novel therapeutic strategy for various cancers.
• TAT-327 enhances the therapeutic potential of peptide 327, demonstrating potent and selective anticancer effects.