Unmodified self antigen triggers human CD8 T cells with stronger tumor reactivity than altered antigen

Abstract

Human cancer vaccines are often prepared with altered “analog” or “heteroclitic” antigens that have been optimized for HLA class I binding, resulting in enhanced immunogenicity. Here, we take advantage of CpG oligodeoxynucleotides as powerful vaccine adjuvants and demonstrate the induction of high T cell frequencies in melanoma patients, despite the use of natural (unmodified) tumor antigenic peptide. Compared with vaccination with analog peptide, natural peptide induced T cell frequencies that were approximately twofold lower. However, T cells showed superior tumor reactivity because of ( i ) increased functional avidity for natural antigen and ( ii ) enhancement of T cell activation and effector function. Thus, novel vaccine formulations comprising potent immune stimulators may allow to circumvent the need for modified antigens and can induce highly functional T cells with precise antigen specificity.

Single cell analysis reveals similar functional competence of dominant and nondominant CD8 T-cell clonotypes

“…Similar results were obtained with multimers bearing the native peptide ( Fig. S1B), thus indicating that the two multimers efficiently bound to all Melan-A-specific T cells with similar fine specificity to analogue or native peptide, in line with our previous report (10).…”

“…Fifteen HLA-A*0201-positive patients with stage III/IV metastatic melanoma were included in a phase I prospective trial at the Ludwig Institute for Cancer Research and the Multidisciplinary Oncology Center, which was approved by institutional review boards and regulatory agencies (9,10). Patients received monthly low-dose vaccinations whereby they were injected s.c. with 100 μg of the Melan-A MART-1 26-35 unmodified native peptide (EAAGIGILTV) or the Melan-A MART-1 26-35 analogue A27L peptide (ELA-GIGILTV), mixed with 0.5 mg CpG-ODN 7909/PF-3512676 (Pfizer/Coley Pharmaceutical Group) and emulsified in IFA (Montanide ISA-51; Seppic) (9).…”

“…This vaccine consistently induced strong T-cell responses that were easily detectable by direct ex vivo analysis (9), not only when the Melan-A A27L analogue peptide (optimized for enhanced HLA-A*0201 binding) was used for vaccination, but also with the weakly antigenic native peptide (10). We have previously shown that the native peptide induced T-cell responses with increased capacity to recognize tumor cells and increased overall T-cell functionality (10). Here, we demonstrate that this superior tumor reactivity was associated with enhanced effector cell activation of nearly all individual T cells.…”

“…The patients with melanoma had received potent lowdose synthetic vaccines composed of Melan-A 26-35 peptide, CpG-ODN 7909, and incomplete Freund adjuvant (IFA). This vaccine consistently induced strong T-cell responses that were easily detectable by direct ex vivo analysis (9), not only when the Melan-A A27L analogue peptide (optimized for enhanced HLA-A*0201 binding) was used for vaccination, but also with the weakly antigenic native peptide (10). We have previously shown that the native peptide induced T-cell responses with increased capacity to recognize tumor cells and increased overall T-cell functionality (10).…”

Vaccination‐induced functional competence of circulating human tumor‐specific CD8 T‐cells

“…In contrast, the natural peptide triggered T-cells with higher functional avidity TCRs and enhanced IFNc production. 43 However, a minority of patients responded only very weakly to the natural peptide. In this study, 10/24 patients were vaccinated with the natural, and 14/24 patients with the analog peptide (Supporting Information Table 1A).…”