Identification of GP100‐derived, melanoma‐specific cytotoxic T‐lymphocyte epitopes restricted by HLA‐A3 supertype molecules by primary in vitro immunization with peptide‐pulsed dendritic cells

Abstract

The human melanocyte lineage-specific antigen gp100 contains several epitopes recognized by cytotoxic T lymphocytes (CTL). However, most of the epitopes reported to date are HLA-A2.1-restricted. Despite the high frequency of HLA-A2.1 in melanoma patients, effective population coverage requires the identification of epitopes restricted by other frequent HLA alleles. Herein, HLA-A3 binding, gp100-derived synthetic peptides were tested for their capacity to elicit anti-melanoma CTL in vitro using CD8 ؉ T cells from healthy donors as responders and peptide-pulsed autologous dendritic cells as antigen-presenting cells. Of 7 peptides tested, 2 (gp100[9 87 ] and gp100[10 86 ] ) induced CTLs that killed melanoma cell lines expressing HLA-A3 and gp100. Additional MHC-binding studies to various HLA molecules belonging to the HLA-A3 superfamily (HLA-A*1101, -A*3101, -A*3301 and -A*6801) were performed to determine whether these CTL epitopes could further increase potential population coverage. Further experiments indicated that the peptide gp100[9 87 ], which bound to HLA-A11 with high affinity, was capable of inducing specific CTLs that killed melanoma cells expressing gp100 and HLA-A11 molecules. Our results indicate that the gp100[9 87 ] peptide corresponds to a CTL epitope which may be restricted by either the HLA-A3 or HLA-A11 allele, emphasizing its utility for the design and development of epitope-based therapies for melanoma. Int.

Identification of epidermal growth factor receptor-derived peptides immunogenic for HLA-A2+ cancer patients

“…both cancer patients and HDs, whereas humoral responses to those HER2/neu peptides were not reported (Fisk et al, 1995;Peoples et al, 1995;Kawashima et al, 1999;Okugawa et al, 2000). It is of note, however, that at least one-third of PBMCs and sera samples from epithelial cancer patients in the present study showed both cellular and humoral responses to these two peptides, suggesting that these peptides have higher immunogenecity than any of the remaining 27 EGFR-derived peptides, which triggered immune responses only in a few subjects.…”

“…In addition, cytotoxic T lymphocyte (CTL)-directed epitopes could be another class of compound useful in EGFR-targeted therapies as peptide vaccines for cancer patients whose tumours overexpress EGFR. However, there is little information on CTL-directed epitopes of EGFR, although such CTL-directed peptides of HER2/neu, a family of EGFR, have been reported over the past decade (Fisk et al, 1995;Peoples et al, 1995;Kawashima et al, 1999;Okugawa et al, 2000). In previous clinical studies, we reported that some CTL-directed peptides from nonmutated proliferationrelated proteins had the ability to elicit both cellular and humoral immune responses in vivo Noguchi et al, 2003;Sato et al, 2003).…”

Development of a live and highly attenuated Listeria monocytogenes-based vaccine for the treatment of Her2/neu-overexpressing cancers in human

“…The chimeric protein harbors most of the known human MHC class I epitopes of the protein. 13,14 The ChHer2 gene was excised from the plasmid, pAdv138 (which was used to construct Lm-LLO-ChHer2) and cloned into LmddA shuttle plasmid, resulting in the plasmid pAdv164 ( Figure 1a). There are two major differences between these two plasmid backbones.…”

Immunology and immunotherapy approaches for prostate cancer

“…44 (3) Class I HLA-restricted widely expressed antigens -genes encode widely expressed tumour antigens that are detected in many normal and tumour tissues with no favoured expression on a certain cancer; for example, carcinoembryonic antigen, which is expressed on colon, breast, lung and gastric carcinomas and on normal gastrointestinal and embryonic tissue. 45 (4) Class I HLArestricted, tumour-specific antigens -they are unique tumour antigens that arise from mutations of normal genes such as cyclin-dependent kinase 4 and b-catenin. 46,47 (5) Class II HLA-restricted antigens -identification of tumour epitopes recognized by CD4 þ T lymphocytes can be a critical approach for improving antitumour immune responses.…”