Large T cell clones expressing immune checkpoints increase during multiple myeloma evolution and predict treatment resistance

Cirino Botta (), Cristina Perez, Marta Larrayoz, Noemi Puig, Maria-Teresa Cedena, Rosalinda Termini, Ibai Goicoechea, Sara Rodriguez, Aintzane Zabaleta, Aitziber Lopez, Sarai Sarvide, Laura Blanco, Daniele M. Papetti, Marco S. Nobile, Daniela Besozzi, Massimo Gentile, Pierpaolo Correale, Sergio Siragusa, Albert Oriol, Maria Esther González-Garcia, Anna Sureda, Felipe de Arriba, Rafael Rios Tamayo, Jose-Maria Moraleda, Mercedes Gironella, Miguel T. Hernandez, Joan Bargay, Luis Palomera, Albert Pérez-Montaña, Hartmut Goldschmidt, Hervé Avet-Loiseau, Aldo Roccaro, Alberto Orfao, Joaquin Martinez-Lopez, Laura Rosiñol, Juan-José Lahuerta, Joan Blade, Maria-Victoria Mateos, Jesús F. San-Miguel, Jose-Angel Martinez Climent and Bruno Paiva ()
Additional contact information
Cirino Botta: University of Palermo
Cristina Perez: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), CCUN, Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC numbers CB16/12/00369, CB16/12/00489
Marta Larrayoz: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), CCUN, Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC numbers CB16/12/00369, CB16/12/00489
Noemi Puig: Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca (IBSAL), Centro de Investigación del Cancer (IBMCC-USAL, CSIC), CIBER-ONC number CB16/12/00233
Maria-Teresa Cedena: Hospital Universitario 12 de Octubre, CIBER-ONC number CB16/12/00369
Rosalinda Termini: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), CCUN, Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC numbers CB16/12/00369, CB16/12/00489
Ibai Goicoechea: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), CCUN, Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC numbers CB16/12/00369, CB16/12/00489
Sara Rodriguez: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), CCUN, Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC numbers CB16/12/00369, CB16/12/00489
Aintzane Zabaleta: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), CCUN, Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC numbers CB16/12/00369, CB16/12/00489
Aitziber Lopez: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), CCUN, Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC numbers CB16/12/00369, CB16/12/00489
Sarai Sarvide: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), CCUN, Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC numbers CB16/12/00369, CB16/12/00489
Laura Blanco: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), CCUN, Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC numbers CB16/12/00369, CB16/12/00489
Daniele M. Papetti: University of Milano-Bicocca
Marco S. Nobile: Ca’ Foscari University of Venice
Daniela Besozzi: University of Milano-Bicocca
Massimo Gentile: “Annunziata” Hospital
Pierpaolo Correale: Great Metropolitan Hospital “Riuniti” of Reggio Calabria
Sergio Siragusa: University of Palermo
Albert Oriol: Institut Català d’Oncologia i Institut Josep Carreras
Maria Esther González-Garcia: Hospital de Cabueñes
Anna Sureda: Institut Català d’Oncologia-Hospitalet, Instituto de Investigación Biomédica de Bellvitge (IDIBELL)
Felipe de Arriba: Hospital Morales Meseguer, IMIB-Arrixaca, Universidad de Murcia
Rafael Rios Tamayo: Hospital Universitario Puerta de Hierro
Jose-Maria Moraleda: Hospital Morales Meseguer, IMIB-Arrixaca, Universidad de Murcia
Mercedes Gironella: Hospital Vall d’Hebron
Miguel T. Hernandez: Hospital Universitario de Canarias
Joan Bargay: Hospital Son Llatzer
Luis Palomera: Hospital Clínico Lozano Blesa
Albert Pérez-Montaña: Hospital Son Espases
Hartmut Goldschmidt: University of Heidelberg
Hervé Avet-Loiseau: IUC-T Oncopole
Aldo Roccaro: ASST Spedali Civili di Brescia
Alberto Orfao: CIBER-ONC number CB16/12/00400
Joaquin Martinez-Lopez: Hospital Universitario 12 de Octubre, CIBER-ONC number CB16/12/00369
Laura Rosiñol: Hospital Clínic IDIBAPS
Juan-José Lahuerta: Hospital Universitario 12 de Octubre, CIBER-ONC number CB16/12/00369
Joan Blade: Hospital Clínic IDIBAPS
Maria-Victoria Mateos: Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca (IBSAL), Centro de Investigación del Cancer (IBMCC-USAL, CSIC), CIBER-ONC number CB16/12/00233
Jesús F. San-Miguel: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), CCUN, Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC numbers CB16/12/00369, CB16/12/00489
Jose-Angel Martinez Climent: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), CCUN, Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC numbers CB16/12/00369, CB16/12/00489
Bruno Paiva: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), CCUN, Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC numbers CB16/12/00369, CB16/12/00489

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Tumor recognition by T cells is essential for antitumor immunity. A comprehensive characterization of T cell diversity may be key to understanding the success of immunomodulatory drugs and failure of PD-1 blockade in tumors such as multiple myeloma (MM). Here, we use single-cell RNA and T cell receptor sequencing to characterize bone marrow T cells from healthy adults (n = 4) and patients with precursor (n = 8) and full-blown MM (n = 10). Large T cell clones from patients with MM expressed multiple immune checkpoints, suggesting a potentially dysfunctional phenotype. Dual targeting of PD-1 + LAG3 or PD-1 + TIGIT partially restored their function in mice with MM. We identify phenotypic hallmarks of large intratumoral T cell clones, and demonstrate that the CD27− and CD27+ T cell ratio, measured by flow cytometry, may serve as a surrogate of clonal T cell expansions and an independent prognostic factor in 543 patients with MM treated with lenalidomide-based treatment combinations.

Date: 2023
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DOI: 10.1038/s41467-023-41562-6

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