title: Enhanced anti-colon cancer immune responses with modified eEF2-derived peptides.
abstract: Eukaryotic elongation factor-2 (eEF2) is overexpressed in many human cancers and is an attractive target for cancer immunotherapy. The eEF2 derived polypeptides have been shown to be able to induce cytotoxic T lymphocytes from healthy donor. Here, we demonstrate the evidence indicating that modification of a segment of peptides from wild type eEF2-derived immunogenic peptides is able to further enhance its capacity of inducing antigen-specific cytotoxic T lymphocytes (CTLs) against colon cancer cells. Using peptide-MHC binding algorithms, potential HLA-A2.1-restricted epitopes capable of inducing specific CD8(+) CTLs were identified. By analyzing HLA-A2.1 affinity and immunogenicity, we further identified one novel immunogenic peptide, P739-747 (RLMEPIYLV), that elicited specific CTL responses in HLA-A2.1/K(b) transgenic mice and culture with peripheral blood lymphocytes from colon cancer patients. Furthermore, replacing certain amino acids (at positions 1, 3, 7) within the P739-747 sequence improved the immunogenicity against eEF2. Several analogs containing the auxiliary HLA-A*0201 anchor residues were able to stably bind to HLA-A*0201 and enhance CTL responses compared with the native sequence; two of them showed increased anti-tumor effects during the adoptive immunotherapy in vivo. Thus, these results support that modified immunogenic analogs are promising candidates for peptide-based cancer vaccination and immunotherapy.
authors: Biotherapy Center, The Second Affiliated Hospital, Qingdao University Medical College, Qingdao 266042, China. Electronic address: sunweihong@126.com.
authors: Weihong
authors: W
authors: Sun
authors: Biotherapy Center, The Second Affiliated Hospital, Qingdao University Medical College, Qingdao 266042, China.
authors: Xiaofang
authors: X
authors: Wei
authors: Department of Clinical Laboratory, The Second Affiliated Hospital, Qingdao University Medical College, Qingdao 266042, China.
authors: Airong
authors: A
authors: Niu
authors: Department of Oncology, The Second Affiliated Hospital, Qingdao University Medical College, Qingdao 266042, China.
authors: Xuezhen
authors: X
authors: Ma
authors: Department of Radiation Oncology, NCI-designated Compressive Cancer Center, University of California Davis, Sacramento, CA 95817, USA. Electronic address: jijli@ucdavis.edu.
authors: Jian Jian
authors: JJ
authors: Li
authors: Biotherapy Center, The Second Affiliated Hospital, Qingdao University Medical College, Qingdao 266042, China.
authors: Daiqing
authors: D
authors: Gao
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D003110:Colonic Neoplasms / Q000276:immunology / Q000628:therapy*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D015789:HLA-A2 Antigen / Q000378:metabolism; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D016219:Immunotherapy, Adoptive; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D020652:Peptide Elongation Factor 2 / Q000737:chemistry; D010446:Peptide Fragments / Q000494:pharmacology*; D011485:Protein Binding; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects*
chemical_list: D015789:HLA-A2 Antigen; D007155:Immunologic Factors; D020652:Peptide Elongation Factor 2; D010446:Peptide Fragments
keywords: Adoptive immunotherapy; CTL; Colon cancer; Enhanced immunoresponse; HLA-A2.1-restricted; Modified epitope