Dendritic cells to prevent cancer: Immune responses against neoantigens after dendritic cell vaccination of Lynch Syndrome patients

Abstract

Abstract Lynch syndrome (LS) is an autosomal dominantly inherited syndrome caused by monoallelic germline aberrations affecting a DNA mismatch repair (MMR) gene, which leads to the development of microsatellite instability. Individuals with LS are 60–80% more prone to colorectal cancer (CRC). MMR deficiency in tumor DNA causes shifts in the translational reading frame resulting in the production of altered peptides called neoantigens. In a phase I/II clinical trial we vaccinated 20 healthy LS mutation carriers and 3 LS patients with surgically resected CRC with monocyte-derived dendritic cells (DC) loaded with neoantigens of TGF-βRII and caspase-5, and CEA. The objective was to analyze the presence and functionality of antigen specific CD8+ T-cells in peripheral blood and biopsies of post-treatment skin tests. Cell lines stably expressing the (neo)antigen were generated and used in calcein based killing assays with expanded (neo)antigen specific patient CD8+ T cells. The vaccination induced antigen specific T cell responses in 20/23 patients. Multifunctional antigen specific T-cells producing multiple cytokines and high amounts of interferon-γ upon peptide stimulation were detectable in peripheral blood. Moreover patient T cells of 3/4 patients tested demonstrated cytotoxicity against tumor cells presenting TGFβRII neoantigen, the T cell receptor repertoires of which had shared motifs in the clonotypes between patients as identified by Illumina MiSeq sequencing. Conclusion-DC vaccination with (neo)antigens is well tolerated in LS patients and induces functional (neo)antigen specific T cells capable of eliciting a cytotoxic immune response thus able to enhance antitumor immunity in a prophylactic and therapeutic setting.