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SERGIO SIRAGUSA

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

  • Authors: Botta, Cirino; Perez, Cristina; Larrayoz, Marta; Puig, Noemi; Cedena, Maria-Teresa; Termini, Rosalinda; Goicoechea, Ibai; Rodriguez, Sara; Zabaleta, Aintzane; Lopez, Aitziber; Sarvide, Sarai; Blanco, Laura; Papetti, Daniele M; Nobile, Marco S; Besozzi, Daniela; Gentile, Massimo; Correale, Pierpaolo; Siragusa, Sergio; Oriol, Albert; González-Garcia, Maria Esther; Sureda, Anna; de Arriba, Felipe; Rios Tamayo, Rafael; Moraleda, Jose-Maria; Gironella, Mercedes; Hernandez, Miguel T; Bargay, Joan; Palomera, Luis; Pérez-Montaña, Albert; Goldschmidt, Hartmut; Avet-Loiseau, Hervé; Roccaro, Aldo; Orfao, Alberto; Martinez-Lopez, Joaquin; Rosiñol, Laura; Lahuerta, Juan-José; Blade, Joan; Mateos, Maria-Victoria; San-Miguel, Jesús F; Martinez Climent, Jose-Angel; Paiva, Bruno
  • Publication year: 2023
  • Type: Articolo in rivista
  • OA Link: http://hdl.handle.net/10447/610273

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.