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

Abstract

Large T cell; Immune checkpoints; Multiple myeloma

Cèl·lules T grans; Punts de control immunitari; Mieloma múltiple

Células T grandes; Puntos de control inmunitario; Mieloma múltiple

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.

This work was supported by grants from the Instituto de Salud Carlos III/Subdireccion General de Investigacion Sanitaria and co-financed by FEDER funds (CB16/12/00233, CB16/12/00369, PI17/01243, PI19/00818 and PI20/00048), and together with Fundación Científica de la Asociación Española Contra el Cáncer (FCAECC) for iMMunocell Transcan-2 (AC17/00101), FCAECC Predoctoral Grant Junta Provincial Navarra, the Cancer Research UK (C355/A26819), FCAECC and Italian Association for Cancer Research (AIRC) under the Accelerator Award Program (EDITOR), 2017 Multiple Myeloma Research Foundation Immunotherapy Networks of Excellence, Black Swan Research Initiative of the International Myeloma Foundation, European Hematology Association nonclinical advanced research grant (3680644), European Research Council 2015 Starting Grant (MYELOMANEXT grant 680200), the Cancer Research Innovation in Science Cancer Foundation (PR_EX_2020-02), the Leukemia Lymphoma Society, unrestricted grants from Bristol-Myers Squibb/Celgene and Takeda, Roche imCORE program (NAV-4 and NAV-15), Fondazione Regionale per la Ricerca Biomedica (Regione Lombardia) (Project ID 065 JTC 2016), ERA-NET TRANSCAN-2, and by My First AIRC Grant 2020 (n. 24534, 2021/2026), and by the Riney Family Multiple Myeloma Research Program Fund.