421 Interaction-dependent identification of tumor-specific antigen T cells for enhanced adoptive therapy in HNSCC

Le résumé fourni par la source

Background Head and neck squamous cell carcinomas (HNSCCs) represent the sixth most common cancer worldwide with an estimated 65,630 cases and 14,500 deaths in the United States last year. Fortuitously, by virtue of their high mutational burden and robust neoantigenome, HNSCCs harbor an abundance of tumor-specific antigen (TSA)-T cells; and, thus, represent an ideal target for autologous adoptive therapy. However, the lack of a reliable biomarker to accurately identify bona fide TSA-T cells among a heterogenous population of tumor-infiltrating lymphocytes (TILs) has precluded the complete translation of this otherwise promising therapeutic strategy. Methods We developed an interaction-based chemoenzymatic labeling method to rapidly and efficiently identify TSA-T cells: the α-(1,3)-fucosyltransferase–FucoID–strategy. Using the FucoID method, we profiled TSA-T cells identified by proximity-based chemoenzymatic labeling (figure 1). Results We find that FucoID labeled T cells in both the tumor and tumor-draining lymph node compartments feature a population of TSA-T cells with exhausted-stem cell like phenotypes and robust antitumoral cytotoxic activity. Additionally, when subjected to conventional ex vivo expansion protocols, these FucoID-labeled T cells are resistant to differentiation and anergy following adoptive transfer in vivo. Through tandem T cell receptor (TCR) and transcriptomic sequencing at the single-cell level, FucoID-labeled T cells from the tumor constitute a defined population with potent effector function (figure 2). An analysis of the FucoID-labeled T cells from the draining lymph node that share a TCR repertoire with those from the tumor reveals a unique population with high TCF-7 expression and stem-like features (figure 3). Conclusions The FucoID proximity-based labeling strategy represents a translatable, antigen-agnostic method to exclusively and expediently identify TSA-reactive T cells with phenotypes optimal for ex vivo expansion, in vivo persistence, and antitumor cytotoxicity. This work represents a paradigm shift in the approach to adoptive T cell therapies, which can immediately inform the design of next-generation immune oncology trials for HNSCC.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.