Single-cell characterization of anti-LAG-3 and anti-PD-1 combination treatment in patients with melanoma

Jani Huuhtanen, Henna Kasanen, Katriina Peltola, Tapio Lönnberg, Virpi Glumoff, Oscar Brück, Olli Dufva, Karita Peltonen, Johanna Vikkula, Emmi Jokinen, Mette Ilander, Moon Hee Lee, Siru Mäkelä, Marta Nyakas, Bin Li, Micaela Hernberg, Petri Bono, Harri Lähdesmäki, Anna Kreutzman, Satu Mustjoki

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Abstract

BackgroundRelatlimab plus nivolumab (anti-lymphocyte-activation gene 3 plus anti-programmed death 1 [anti-LAG-3+anti-PD-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.MethodsWe evaluated blood samples from 40 immunotherapy-naive or prior immunotherapy-refractory patients with metastatic melanoma treated with anti-LAG-3+anti-PD-1 in a phase I trial using single-cell RNA and T cell receptor sequencing (scRNA+TCRαβ-Seq) combined with other multiomics profiling.ResultsThe highest LAG3 expression was noted in NK 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. Last, higher baseline TCR clonality was observed in responding patients, and their expanding CD8+ T cell clones gained a more cytotoxic and NK-like phenotype.ConclusionAnti-LAG-3+anti-PD-1 therapy has profound effects on NK cells and Tregs in addition to CD8+ T cells.Trial registrationClinicalTrials.gov (NCT01968109)FundingCancer 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.

Original languageEnglish
Article numbere164809
Number of pages17
JournalJournal of Clinical Investigation
Volume133
Issue number6
DOIs
Publication statusPublished - 15 Mar 2023
MoE publication typeA1 Journal article-refereed

Keywords

  • Humans
  • Programmed Cell Death 1 Receptor
  • Melanoma/drug therapy
  • Nivolumab/therapeutic use
  • Antineoplastic Agents/pharmacology
  • CD8-Positive T-Lymphocytes
  • Receptors, Antigen, T-Cell/metabolism
  • Melanoma, Cutaneous Malignant

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