1228 Comprehensive T-cell Profiling in Chordomas: Single-cell RNA-Seq and TCR Profiling Analysis Uncover Antitumor and Exhaustion Phenotypes for Targeted Immunotherapies

Le résumé fourni par la source

INTRODUCTION: Chordomas, a rare type of tumor, originate from residual notochord tissue. These tumors present important challenges due to the limited treatment options. Investigating the intricacies of T-cell composition and function in chordoma immunity holds the potential to advance immunotherapy strategies for these patients. METHODS: We generated a comprehensive single-cell atlas of T cells of chordomas, incorporating paired single-cell transcriptomic samples from the tumor and blood of five patients and single-cell TCR sequencing data to assess T-cell clonality. Additionally, we analyzed T cells in 33 chordomas (22 newly diagnosed and 11 recurrent tumors) using multiplex immunofluorescence. RESULTS: Our results demonstrate that CD8+ T-cell antitumoral immunity originates in the periphery, marked by clonal expansion of cytotoxic and memory T cells in the blood. However, this immunity experiences progressive exhaustion upon tumor infiltration. Notably, a large percentage of CD8+ T-cells from the tumors and blood shared their TCRs with exhausted CD8+ T-cells known for tumor specificity, confirming the origin of a peripheral antitumor response. We identified specific antigen peptide sequences through TCR analysis that were enriched in exhausted T cell receptors' binding sites that uncovered shared motifs within the reactive tumor-infiltrating compartment. Moreover, we observed that CTLA-expressing central memory and Tregs made up most of the CD4 T-cell tumoral landscape. Interestingly, multiplex immunofluorescence showed a higher abundance of CD3+ T cells in newly diagnosed chordomas compared to recurrent cases. CONCLUSIONS: This study sheds light on the composition and function of T cells in chordomas, revealing the origin and exhaustion of CD8+ T-cell antitumor immunity. These findings contribute to our understanding of chordoma immunity to guide the development of targeted immunotherapies for both newly diagnosed and recurrent cases.

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