TY - JOUR
T1 - Single-cell characterization of anti-LAG-3 and anti-PD-1 combination treatment in patients with melanoma
AU - Huuhtanen, Jani
AU - Kasanen, Henna
AU - Peltola, Katriina
AU - Lönnberg, Tapio
AU - Glumoff, Virpi
AU - Brück, Oscar
AU - Dufva, Olli
AU - Peltonen, Karita
AU - Vikkula, Johanna
AU - Jokinen, Emmi
AU - Ilander, Mette
AU - Lee, Moon Hee
AU - Mäkelä, Siru
AU - Nyakas, Marta
AU - Li, Bin
AU - Hernberg, Micaela
AU - Bono, Petri
AU - Lähdesmäki, Harri
AU - Kreutzman, Anna
AU - Mustjoki, Satu
PY - 2023/3/15
Y1 - 2023/3/15
N2 - 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.
AB - 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.
KW - Humans
KW - Programmed Cell Death 1 Receptor
KW - Melanoma/drug therapy
KW - Nivolumab/therapeutic use
KW - Antineoplastic Agents/pharmacology
KW - CD8-Positive T-Lymphocytes
KW - Receptors, Antigen, T-Cell/metabolism
KW - Melanoma, Cutaneous Malignant
KW - Immunology
KW - T cells
KW - Skin cancer
KW - Oncology
KW - NK cells
U2 - 10.1172/JCI164809
DO - 10.1172/JCI164809
M3 - Article
C2 - 36719749
SN - 0021-9738
VL - 133
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 6
M1 - e164809
ER -