Large T cell clones expressing immune checkpoints increase during multiple myeloma evolution and predict treatment resistance
Cirino Botta, Cristina Pérez, Marta Larráyoz, Noemí Puig, María‐Teresa Cedena, Rosalinda Termini, Ibai Goicoechea, Sara Rodríguez, Aintzane Zabaleta, Aitziber López, Sarai Sarvide, Laura Blanco, Daniele M. Papetti, Marco S. Nobile, Daniela Besozzi, Massimo Gentile, Pierpaolo Correale, Sergio Siragusa, Albert Oriol, María Esther González-García, Anna Sureda, Felipe de Arriba, Rafael Ríos, José M. Moraleda, Mercedes Gironella, Miguel‐Teodoro Hernández, Joan Bargay, Luis Palomera, Albert Pérez-Montaña, Hartmut Goldschmidt, Hervé Avet‐Loiseau, Aldo M. Roccaro, Alberto Órfão, Joaquín Martínez‐López, Laura Rosiñol, Juan José Lahuerta, Joan Bladé, María‐Victoria Mateos, Jesús F. San Miguel, Jose-Angel Martinez Climent, Bruno Paiva, the Programa Para el Estudio de la Terapéutica en Hemopatías Malignas/Grupo Español de Mieloma (PETHEMA/GEM) cooperative group, the iMMunocell study group
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.