Abstract
The identification and characterization of tumor-associated antigens (TAAs) that generate specific cytotoxic T lymphocytes (CTLs) are vital to the development of cancer immunotherapy. The epidermal growth factor receptor (EGFR) pathway substrate 8 gene (Eps8) is involved in regulating cancer progression and might be an ideal antigen. In this study, we searched for novel human leukocyte antigen (HLA)-A*2402-restricted epitopes derived from the Eps8 protein via the HLA-binding prediction algorithm. Among four candidates, peptides 327 (EFLDCFQKF), 534 (KYAKSKYDF) and 755 (LFSLNKDEL) induced peptide-specific CTLs to secrete higher levels of interferon-gamma (IFN-γ) and showed enhanced cytotoxic activity against malignant cancer cells. Our results demonstrated that peptide-specific CTLs showed effective antitumor responses, including upregulation of interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-α), granzyme B and perforin. Treatment with peptide-sensitized peripheral blood mononuclear cells (PBMCs) significantly reduced the tumor growth in vivo compared with the non-peptide-sensitized PBMC treatment. Importantly, our results indicated that peptide 327 may interfere with EGFR signaling by mechanistically disrupting Eps8/EGFR complex formation. We extended this observation that peptide 327 also suppressed the viability of cancer cells, blocked EGFR signal pathway and reduced the expression of downstream targets. Notably, conjugation of peptide 327 to the TAT sequence (TAT-327) resulted in potent antitumor activity and selective insertion into cancer cell membranes, where it adopted a punctate distribution. Furthermore, peptide 327 and TAT-327 displayed anticancer properties in xenograft models. Our results indicated that 327, 534 and 755 were novel HLA-A*2402-restricted epitopes from Eps8. By inhibiting the Eps8/EGFR interaction, peptide 327 and TAT-327 may serve as novel peptide inhibitors, which could provide an innovative approach for treating various cancers.
Highlights
IntroductionTumor-associated antigens (TAAs) are frequently present on various tumor cells but are absent or present at very low levels on normal cells and can be recognized by cytotoxic T lymphocytes (CTLs)[5,6], leading to cytotoxic cellular responses[7]
Cancer is highlighted by the accumulation of a number of genetic variations and the loss of normal cellularImmunotherapy is a promising cancer treatment that has Official journal of the Cell Death Differentiation AssociationXie et al Cell Death and Disease (2018)9:379 emerged with remarkable clinical efficacy, with the evidence that host immune responses can influence patient survival[3,4].Tumor-associated antigens (TAAs) are frequently present on various tumor cells but are absent or present at very low levels on normal cells and can be recognized by cytotoxic T lymphocytes (CTLs)[5,6], leading to cytotoxic cellular responses[7]
Natural T-cell responses against Eps[8] The immune response of T cells to K562 and K562/A24 cells treated with Eps8-derived peptides 327, 534, 334 or 755 (10 μM) was assessed by interferon-gamma (IFN-γ) enzyme-linked immunospot (ELISPOT) assays after we isolated peripheral blood mononuclear cells (PBMCs) from five healthy individuals as well as four patients with cancer (Supplementary Tables 1 and 2)
Summary
Tumor-associated antigens (TAAs) are frequently present on various tumor cells but are absent or present at very low levels on normal cells and can be recognized by cytotoxic T lymphocytes (CTLs)[5,6], leading to cytotoxic cellular responses[7]. While peptide vaccines that elicit a tumor-reactive immune response to TAAs have been under intensive investigation for decades, the number of antigens identified and the efficacy in clinical trials was previously limited[8]. The epidermal growth factor receptor (EGFR) pathway substrate 8 (Eps8) is a TAA that is frequently overexpressed in breast, colon, and pancreatic cancers and other malignancies but rarely in normal tissues[9,10,11,12]. Eps[8] has been considered an attractive target for specific cancer immunotherapy
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