Identification of Promiscuous KIF20A Long Peptides Bearing Both CD4+ and CD8+ T-cell Epitopes: KIF20A-Specific CD4+ T-cell Immunity in Patients with Malignant Tumor

Abstract

Purpose: To identify long peptides (LP) derived from a novel tumor-associated antigen (TAA), kinesin family member 20A (KIF20A), which induce tumor-specific T-helper type 1 (T H 1) cells and CTLs.Experimental Design: We combined information from a recently developed computer algorithm predicting HLA class II-binding peptides with KIF20A-derived CTL-epitope sequences presented by HLA-A2 (A Ã 02:01) or HLA-A24 (A Ã 24:02) to select candidate promiscuous T H 1-cell epitopes containing CTL epitopes. Peripheral blood mononuclear cells (PBMC) derived from healthy donors or patients with head-and-neck malignant tumor (HNMT) were used to study the immunogenicity of KIF20A-LPs, and the in vitro cross-priming potential of KIF20A-LPs bearing CTL epitopes. We used HLA-A24 transgenic mice to address whether vaccination with KIF20A-LP induces efficient cross-priming of CTLs in vivo. The T H 1-cell response to KIF20A-LPs in HNMT patients receiving immunotherapy with TAA-derived CTL-epitope peptides was analyzed using IFN-g enzyme-linked immunospot assays. Results: We identified promiscuous KIF20A-LPs bearing naturally processed epitopes recognized by CD4 þ T cells and CTLs. KIF20A-specific CTLs were induced by vaccination with a KIF20A-LP in vivo. KIF20A expression was detected in 55% of HNMT by immunohistochemistry, and significant frequencies of KIF20A-specific T H 1 cell responses were detected after short-term in vitro stimulation of PBMCs with KIF20A-LPs in 50% of HNMT patients, but not in healthy donors. Furthermore, these responses were associated with KIF20A expression in HNMT tissues. Conclusions: These are the first results showing the presence of KIF20A-specific T H 1 cell responses in HNMT patients and underline the possible utility of KIF20A-LPs for propagation of T H 1 cells and CTLs.

Mapping the HLA ligandome landscape of acute myeloid leukemia: a targeted approach toward peptide-based immunotherapy

“…Notably, three different class II ligands were identified to contain complete, embedded HLA class I peptides, which points to a striking new option for synergistic vaccine design as discussed in recent publications. 53,54 These novel, naturally presented embedded HLA ligands might present optimal vaccine candidates that are recognized by both, CD4 + and CD8 + T cells.…”

Phase II Clinical Trial of Multiple Peptide Vaccination for Advanced Head and Neck Cancer Patients Revealed Induction of Immune Responses and Improved OS

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IgE/FcεRI-Mediated Antigen Cross-Presentation by Dendritic Cells Enhances Anti-Tumor Immune Responses

“…IgE-mediated antigen presentation might be particularly attractive for therapeutic purposes because of the high efficiency for inducing CTL responses via cross-presentation and the ability for simultaneously inducing antigen-specific CD4 + T helper cells (Platzer et al, 2014a). Concomitant induction of CD8 + and CD4 + T cell responses to tumor antigens was shown to improve anti-tumor immunity because synergy between these two T cell types promotes the killing of cancer cells (Tomita et al, 2013). Importantly, we have also previously shown that IgE-mediated antigen uptake by DCs does not induce allergic Th2-type immune responses by itself (Platzer et al, 2014a), which could counteract efficient CTL responses.…”