Identification of CDCA1‐derived long peptides bearing both CD4+ and CD8+ T‐cell epitopes: CDCA1‐specific CD4+ T‐cell immunity in cancer patients. Issue 2 (5th August 2013) - Tomita, Yusuke
Abstract : We recently identified a novel cancer‐testis antigen, cell division cycle associated 1 (CDCA1) using genome‐wide cDNA microarray analysis, and CDCA1‐derived cytotoxic T lymphocyte (CTL)‐epitopes. In this study, we attempted to identify CDCA1‐derived long peptides (LPs) that induce both CD4 + helper T (Th) cells and CTLs. We combined information from a recently developed computer algorithm predicting HLA class II‐binding peptides with CDCA1‐derived CTL‐epitope sequences presented by HLA‐A2 ( A*02:01 ) or HLA‐A24 ( A*24:02 ) to select candidate CDCA1‐LPs encompassing both Th cell epitopes and CTL‐epitopes. We studied the immunogenicity of CDCA1‐LPs and the cross‐priming potential of LPs bearing CTL‐epitopes in both human in vitro and HLA‐class I transgenic mice in vivo . Then we analyzed the Th cell response to CDCA1 in head‐and‐neck cancer (HNC) patients before and after vaccination with a CDCA1‐derived CTL‐epitope peptide using IFN‐γ enzyme‐linked immunospot assays. We identified two CDCA1‐LPs, CDCA139–64 ‐LP and CDCA155–78 ‐LP, which encompass naturally processed epitopes recognized by Th cells and CTLs. CDCA1‐specific CTLs were induced through cross‐presentation of CDCA1‐LPs in vitro and in vivo . In addition, CDCA1‐specific Th cells enhanced induction of CDCA1‐specific CTLs. Furthermore, significant frequencies of CDCA1‐specific Th cell responses were detected after short‐term in vitro stimulation of peripheral blood mononuclear cells (PBMCs) with CDCA1‐LPs in HNC patients (CDCA139–64 ‐LP, 74%; CDCA155–78 ‐LP, 68%), but not in healthy donors. These are the first results demonstrating the presence of CDCA1‐specific Th cell responses in HNC patients and underline the possible utility of CDCA1‐LPs for propagation of both CDCA1‐specific Th cells and CTLs. Abstract : What's new? Tumor immunotherapy often focuses on the induction of cancer‐specific cytotoxic T cells (CTLs). However, T helper cells (Th1) play a critical role in the efficient and long‐lasting induction of functional antitumor CTLs. Here, the authors describe two new peptides derived from the cell division cycle associated 1 (CDCA1) tumor antigen that are efficient in stimulating both a Th1 and a CTL response through cross‐presentation. The two peptides, CDCA139–64 ‐LP and CDCA155–78 ‐LP are longer than conventionally used vaccination peptides and elicited efficient T cell responses after in vitro stimulation of peripheral blood mononuclear cells isolated from head and neck cancer patients but not from healthy individuals. These findings will help refine clinical trials currently ongoing with CDCA1 peptide‐based immunotherapy for lung, breast, prostate and head and neck cancer patients.