Interaction-Dependent Identification of Tumor-Specific Antigen T Cells for Adoptive Therapy in HNSCC

Presentation: S401
Topic: Immunotherapy / Systemic Therapy
Type: Oral
Date: Tuesday, July 11, 2023
Session: 1:30 PM - 3:00 PM Immunotherapy Session 3
Authors: Robert Saddawi-Konefka1; Yujie Shi2; Lauren Clubb1; William Wong1; John Chang1; Peng Wu2; J. Silvio Gutkind1
Institution(s): 1University of California, San Diego; 2Scripps Research Institute

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. Instead, nearly all ongoing clinical trials employ heterogeneous TILs harvested in bulk, most of which harbor non-TSA bystander T cells, often terminally differentiated and anergic. Discovering a high-fidelity biomarker to identify and isolate TSA-T cells from a heterogenous TIL pool is paramount in order to deliver effective, translatable T cell adoptive therapy for HNSCC. We hypothesize that a rapid and high-throughput method for isolating TSA-T cells that feature stem-like, less differentiated phenotypes will maximize the clinical response of adoptive T cell therapy for HNSCC.

To this end, we have developed an interaction-based chemoenzymatic labelling method to rapidly and efficiently identify TSA-T cells: the α-(1,3)-fucosyltransferase– FucoID – strategy. Using the FucoID method, we have profiled TSA-T cells identified by proximity-based chemoenzymatic labelling. We find that FucoID labelled T cells in both the tumor and tumor draining lymph node compartments feature a population of TSA-T cells with an exhausted-stem cell like phenotypes and robust antitumoral cytotoxic activity. Additionally, when subjected to conventional ex vivo expansion protocols, we find that these FucoID-labelled T cells are resistant to differentiation and anergy following adoptive transfer in vivo. Excitingly, through tandem T cell receptor (TCR) and transcriptomic sequencing at the single-cell level, we find that the FucoID-labelled T cells from the tumor constitute a defined population with potent effector function. Moreover, an analysis of the FucoID-labelled 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, which affords a novel, high-resolution mapping of TSA- and bystander-TCR and T cell states in HNSCC. Lastly, we find that adoptive transfer of FucoID T cells into tumor-bearing animals robustly respond to PD-1 immune checkpoint inhibition to control disease progression.

We demonstrate that the FucoID proximity-based labelling 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. Overall, 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.