PMID- 29515106 OWN - NLM STAT- MEDLINE DCOM- 20191028 LR - 20191028 IS - 2041-4889 (Electronic) VI - 9 IP - 3 DP - 2018 Mar 7 TI - A dual-function epidermal growth factor receptor pathway substrate 8 (Eps8)-derived peptide exhibits a potent cytotoxic T lymphocyte-activating effect and a specific inhibitory activity. PG - 379 LID - 10.1038/s41419-018-0420-5 [doi] LID - 379 AB - 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-gamma) 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-alpha), 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. FAU - Xie, Xiaoling AU - Xie X AD - Department of Hematology, Zhujiang Hospital, Southern Medical University, No. 253 GongyeDadaoZhong, Guangzhou, Guangdong, 510282, China. FAU - Zhou, Weijun AU - Zhou W AD - Department of Hematology, Zhujiang Hospital, Southern Medical University, No. 253 GongyeDadaoZhong, Guangzhou, Guangdong, 510282, China. FAU - Hu, Yuxing AU - Hu Y AD - Department of Hematology, Zhujiang Hospital, Southern Medical University, No. 253 GongyeDadaoZhong, Guangzhou, Guangdong, 510282, China. FAU - Chen, Yiran AU - Chen Y AD - Department of Hematology, Zhujiang Hospital, Southern Medical University, No. 253 GongyeDadaoZhong, Guangzhou, Guangdong, 510282, China. FAU - Zhang, Honghao AU - Zhang H AD - Department of Hematology, Zhujiang Hospital, Southern Medical University, No. 253 GongyeDadaoZhong, Guangzhou, Guangdong, 510282, China. FAU - Li, Yuhua AU - Li Y AUID- ORCID: 0000-0002-0982-6680 AD - Department of Hematology, Zhujiang Hospital, Southern Medical University, No. 253 GongyeDadaoZhong, Guangzhou, Guangdong, 510282, China. liyuhua1974@outlook.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180307 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Antigens, Neoplasm) RN - 0 (EPS8 protein, human) RN - 0 (Peptides) RN - 82115-62-6 (Interferon-gamma) RN - EC 2.7.10.1 (ErbB Receptors) SB - IM MH - Adaptor Proteins, Signal Transducing/*chemistry MH - Animals MH - Antigens, Neoplasm/metabolism MH - Cell Line MH - Cell Line, Tumor MH - ErbB Receptors/*metabolism MH - HT29 Cells MH - Humans MH - Interferon-gamma/metabolism MH - Mice MH - Mice, Inbred BALB C MH - Mice, Nude MH - Peptides/chemistry/*pharmacology MH - Signal Transduction/drug effects MH - T-Lymphocytes, Cytotoxic/metabolism PMC - PMC5841361 COIS- The authors declare that they have no conflict of interest. EDAT- 2018/03/09 06:00 MHDA- 2019/10/29 06:00 PMCR- 2018/03/07 CRDT- 2018/03/09 06:00 PHST- 2017/10/08 00:00 [received] PHST- 2018/02/12 00:00 [accepted] PHST- 2018/02/08 00:00 [revised] PHST- 2018/03/09 06:00 [entrez] PHST- 2018/03/09 06:00 [pubmed] PHST- 2019/10/29 06:00 [medline] PHST- 2018/03/07 00:00 [pmc-release] AID - 10.1038/s41419-018-0420-5 [pii] AID - 420 [pii] AID - 10.1038/s41419-018-0420-5 [doi] PST - epublish SO - Cell Death Dis. 2018 Mar 7;9(3):379. doi: 10.1038/s41419-018-0420-5.