Single-cell characterization of anti-LAG3+anti-PD1 treatment in melanoma patients

Abstract

Background: Relatlimab+nivolumab (anti-LAG3+anti-PD1) has been approved by FDA as a 1st-line therapy in stage III/IV melanoma, but its detailed effect on the immune system is unknown. Methods: We evaluated blood samples from 40 immunotherapy-naïve or prior immunotherapy-refractory patients with metastatic melanoma treated with anti-LAG3+anti-PD1 in a phase I trial (NCT01968109) using single-cell RNA and T cell receptor (TCR) sequencing (scRNA+TCRαβ-seq) combined with other multiomics profiling. Results: The highest LAG3 expression was noted in NK cells, regulatory T cells (Tregs), and CD8+ T cells, and these cell populations underwent the most significant changes during the treatment. Adaptive NK cells were enriched in responders and underwent profound transcriptomic changes during the therapy resulting in an active phenotype. LAG3+ Tregs expanded but based on the transcriptome profile became metabolically silent during the treatment. Lastly, higher baseline TCR clonality was observed in responding patients, and their expanding CD8+ T cell clones gained more cytotoxic and NK-like phenotype. Conclusion: Anti-LAG3+anti-PD1 therapy has profound effects on NK cells and Tregs in addition to CD8+ T cells.