2 research outputs found
Systematic drug screening reveals specific vulnerabilities and co-resistance patterns in endocrine-resistant breast cancer
Single-cell characterization of antiâLAG-3 and antiâPD-1 combination treatment in patients with melanoma
Abstract
Background: Relatlimab plus nivolumab (antiâlymphocyte-activation gene 3 plus antiâprogrammed death 1 [antiâLAG-3+antiâPD-1]) has been approved by the FDA as a first-line therapy for stage III/IV melanoma, but its detailed effect on the immune system is unknown.
Methods: We evaluated blood samples from 40 immunotherapy-naive or prior immunotherapyârefractory patients with metastatic melanoma treated with antiâLAG-3+antiâPD-1 in a phase I trial using single-cell RNA and T cell receptor sequencing (scRNA+TCRαÎČ-Seq) combined with other multiomics profiling.
Results: The highest LAG3 expression was noted in NK cells, Tregs, and CD8âș 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. LAG3âș Tregs expanded, but based on the transcriptome profile, became metabolically silent during the treatment. Last, higher baseline TCR clonality was observed in responding patients, and their expanding CD8âș T cell clones gained a more cytotoxic and NK-like phenotype.
Conclusion: AntiâLAG-3+antiâPD-1 therapy has profound effects on NK cells and Tregs in addition to CD8âș T cells.
Trial registration: ClinicalTrials.gov (NCT01968109)
Funding : Cancer Foundation Finland, Sigrid Juselius Foundation, Signe and Ane Gyllenberg Foundation, Relander Foundation, State funding for university-level health research in Finland, a Helsinki Institute of Life Sciences Fellow grant, Academy of Finland (grant numbers 314442, 311081, 335432, and 335436), and an investigator-initiated research grant from BMS