Huuhtanen, J., Kasanen, H., Peltola, K., Lönnberg, T., Glumoff, V., Brück, O., Dufva, O., Peltonen, K., Vikkula, J., Jokinen, E., Ilander, M., Lee, M. H., Mäkelä, S., Nyakas, M., Li, B., Hernberg, M., Bono, P., Lähdesmäki, H., Kreutzman, A., & Mustjoki, S. (2023). Single-cell characterization of anti–LAG-3 and anti–PD-1 combination treatment in patients with melanoma. Journal of Clinical Investigation, 133(6), e164809. https://doi.org/10.1172/JCI164809
Single-cell characterization of anti–LAG-3 and anti–PD-1 combination treatment in patients with melanoma
|Author:||Huuhtanen, Jani1,2,3,4; Kasanen, Henna1,2,4; Peltola, Katriina4,5;|
1Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland
2Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
3Department of Computer Science, Aalto University, Espoo, Finland
4iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland
5Department of Oncology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
6Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
7Research Unit of Biomedicine, Medical Microbiology and Immunology, University of Oulu, Oulu, Finland
8Oslo University Hospital-Radiumhospitalet, Oslo, Norway
9Bristol Myers Squibb (BMS) Research and Development, Princeton, New Jersey, USA
|Online Access:||PDF Full Text (PDF, 3 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe20230925136642
American Society for Clinical Investigation,
|Publish Date:|| 2023-09-25
Background: Relatlimab 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.
Methods: We 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.
Results: The 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.
Conclusion: Anti–LAG-3+anti–PD-1 therapy has profound effects on NK cells and Tregs in addition to CD8⁺ 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.
Journal of clinical investigation
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
1182 Biochemistry, cell and molecular biology
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.
© 2023, Huuhtanen et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.