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1. Unleashing anti-tumor immunity of neoantigen vaccines with intra-tumor vaccination; 2. Reshaping of human B-cell memory by allergen immunotherapy; 3. MHC class I presentation in the context of cancer immunotherapy

国際共・共拠点セミナー

開催情報

開催日時 2024年11月7日(木)14:00~17:00
開催場所 1号館講堂
演者 Peter D. Katsikis, Menno van Zelm, Christopher Schliehe
所属・職名 Erasmus MC/Professor and Head of the Department of Immunology Infection and Immunity Research Group (IIG)・Erasmus MC/Head Laboratory for Humoral Immune Memory・Erasmus MC/Assistant Professor
国名 オランダ
演題 1. Unleashing anti-tumor immunity of neoantigen vaccines with intra-tumor vaccination; 2. Reshaping of human B-cell memory by allergen immunotherapy; 3. MHC class I presentation in the context of cancer immunotherapy
使用言語 英語
世話人 石井 健

概要

1.Although therapeutic cancer vaccines hold promise as a cancer treatment, they have yet to prove their efficacy. Targeting neoantigen, antigens arising from tumor mutations, presents an attractive strategy to steer immunity against cancer while sparing healthy tissues. Using our vaccine formulation that consists of synthetic long peptides and a combination of TLR9 and STING agonists as adjuvant, we have explored ways to improve vaccine efficacy. We find that neopeptide vaccination delivered both subcutaneously and intra-tumorally potently inhibits tumor growth and improves survival in animal models. This vaccination approach induces characteristic changes within the tumor and can serve as a promising vaccination platform for cancer vaccines.
2.IgE-mediated allergies are prevalent disorders and can lead to high morbidity and  life-threatening hypersensitivity reactions. The only available disease-modifying treatment is allergen immunotherapy (AIT). Despite being practiced for >110 years, AIT is not always successful, and the mechanism of action remains poorly understood Recently, a subset of type 2 memory B cells (Bmem) has been defined that seems to be poised to generate IgE responses. In my team, we developed strategies to produce recombinant allergen tetramers for identification of allergen-specific Bmem, and applied these to examine their phenotype, transcriptome and epitope specificity. I will present recent data from my team on allergen-specific Bmem in well-defined cohorts of patients sensitized to bee venom, grass pollen and house dust mite, and how these are affected by short- and long-term allergen immunotherapy. These insights are important to understand what kind of immune changes are needed for sustained unresponsiveness, and how other interventions, e.g. with biologicals, could be used to expedite this.
3.Antigen presentation on major histocompatibility complex (MHC) class I is key for cancer immune surveillance by cytotoxic T-lymphocytes (CTLs). While great progress in enhancing CTL effector function has been made in the fields of immune checkpoint blockade, cancer vaccination, and adoptive T-cell therapy, major obstacles remain that limit the efficacy of current cancer immunotherapies. Critical parameters include the identification of optimal tumor (neo)antigens, the development of potent adjuvants to prime anti-cancer T-cell immunity, the inhibitory tumor microenvironment, and immune evasion through impaired MHC class I presentation on cancer cells. In this presentation, I will outline three unpublished projects covering different bottlenecks within the cancer immunity cycle. I will start by introducing a genome-wide CRISPR/Cas9 screen that we
recently performed to uncover novel regulators of direct MHC class I presentation in the context of cancer immune evasion. Specifically, we uncovered small nuclear ribonucleoprotein polypeptide A (Snrpa) as a novel regulator of tonic MHC class I presentation that modulates expression levels of specific interferon regulatory factors (IRFs). In the second part, I will introduce a novel concept of how to enhance the MHC class I presentation of cancer antigens for better immune surveillance of MHClow tumors. We obtained evidence that small molecule proteolysis-targeting chimeras (PROTACs) boost MHC class I presentation by inducing targeted antigen degradation. In the final part, I will demonstrate the importance of non-canonical antigens as targets for cancer immunotherapy. We recently showed that translation initiation at non-AUG start codons was enhanced by Toll-like receptor (TLR) stimulation. Moreover, the expression of non-AUG-initiated antigens was able to induce tumor regression in mice. Together, the results presented here might contribute to the development of novel treatment options for patients with cancer.