A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells

TLDR

T cell responses to tumor‑encoded missense mutations—neoantigens—have been observed in melanoma, yet a systematic assessment of their immunogenicity is lacking. The study aimed to determine whether a dendritic cell vaccine could enhance neoantigen‑specific T cell immunity in melanoma patients. The vaccine expanded neoantigen‑specific T cell responses, uncovered new HLA‑A*02:01‑restricted neoantigens, and broadened the TCR repertoire, demonstrating enhanced breadth and diversity of antitumor immunity.

Abstract

T cell immunity directed against tumor-encoded amino acid substitutions occurs in some melanoma patients. This implicates missense mutations as a source of patient-specific neoantigens. However, a systematic evaluation of these putative neoantigens as targets of antitumor immunity is lacking. Moreover, it remains unknown whether vaccination can augment such responses. We found that a dendritic cell vaccine led to an increase in naturally occurring neoantigen-specific immunity and revealed previously undetected human leukocyte antigen (HLA) class I-restricted neoantigens in patients with advanced melanoma. The presentation of neoantigens by HLA-A*02:01 in human melanoma was confirmed by mass spectrometry. Vaccination promoted a diverse neoantigen-specific T cell receptor (TCR) repertoire in terms of both TCR-β usage and clonal composition. Our results demonstrate that vaccination directed at tumor-encoded amino acid substitutions broadens the antigenic breadth and clonal diversity of antitumor immunity.