Decreased specific CD8⁺ T cell cross‐reactivity of antigen recognition following vaccination with Melan‐A peptide

Abstract

The aim of T cell vaccines is the expansion of antigen-specific T cells able to confer immune protection against pathogens or tumors. Although increase in absolute cell numbers, effector functions and TCR repertoire of vaccine-induced T cells are often evaluated, their reactivity for the cognate antigen versus their cross-reactive potential is rarely considered. In fact, little information is available regarding the influence of vaccines on T cell fine specificity of antigen recognition despite the impact that this feature may have in protective immunity. To shed light on the cross-reactive potential of vaccine-induced cells, we analyzed the reactivity of CD8 + T cells following vaccination of HLA-A2 + melanoma patients with Melan-A peptide, incomplete Freund's adjuvant and CpG-oligodeoxynucleotide adjuvant, which was shown to induce strong expansion of Melan-A-reactive CD8 + T cells in vivo. A collection of predicted Melan-A cross-reactive peptides, identified from a combinatorial peptide library, was used to probe functional antigen recognition of PBMC ex vivo and Melan-A-reactive CD8 + T cell clones. While Melan-A-reactive CD8 + T cells prior to vaccination are usually constituted of widely cross-reactive naive cells, we show that peptide vaccination resulted in expansion of memory T cells displaying a reactivity predominantly restricted to the antigen of interest. Importantly, these cells are tumor-reactive.

Profile of a Serial Killer: Cellular and Molecular Approaches to Study Individual Cytotoxic T‐Cells following Therapeutic Vaccination

“…The high sensitivity of this method makes it suitable for ex vivo analyses of populations with low frequencies of antigen-specific T-cells and of precious samples (PBMC, TIL, TILN). Moreover it has been used for the characterization of fine antigen-specificity and cross-reactivity on Melan-A-specific T-cell clones [69] using a library of peptides predicted to be potentially cross-reactive with the Melan-A peptide [70]. The authors showed that increased differentiation of derived clones was associated with a decrease in TCR cross-reactivity and an increased specificity against the native Melan-A peptide [69].…”

Progression of Lung Cancer Is Associated with Increased Dysfunction of T Cells Defined by Coexpression of Multiple Inhibitory Receptors

“…In contrast with circulating tumor antigen-specific T cells, which have full functional competence (1,2), T cells with the same antigen specificity residing in the tumor are functionally tolerant with severely impaired inflammatory and cytotoxic functions (1,(3)(4)(5). The functional impairment comprising T-cell exhaustion was originally described in the context of murine chronic lymphocytic choriomeningitis virus (LCMV) infection (6,7), but has been observed also in human chronic infections (8).…”

Local immunomodulation combined to radiofrequency ablation results in a complete cure of local and distant colorectal carcinoma

“…21 The lymphocytes CD8 + T infiltrating tumors are the only the ones expressing PD-1 phenotype. 22 In addition, vaccination strategies have been shown to stimulate antigen-specific CD8 + T cells in patients with tumors. However, these CD8 + T cells remain hypo-responsive at the tumor site and cannot eradicate the tumor.…”