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

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.

SUBMITTER: Botta C

PROVIDER: S-EPMC10511411 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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

Botta Cirino C Perez Cristina C Larrayoz Marta M Puig Noemi N Cedena Maria-Teresa MT Termini Rosalinda R Goicoechea Ibai I Rodriguez Sara S Zabaleta Aintzane A Lopez Aitziber A Sarvide Sarai S Blanco Laura L Papetti Daniele M DM Nobile Marco S MS Besozzi Daniela D Gentile Massimo M Correale Pierpaolo P Siragusa Sergio S Oriol Albert A González-Garcia Maria Esther ME Sureda Anna A de Arriba Felipe F Rios Tamayo Rafael R Moraleda Jose-Maria JM Gironella Mercedes M Hernandez Miguel T MT Bargay Joan J Palomera Luis L Pérez-Montaña Albert A Goldschmidt Hartmut H Avet-Loiseau Hervé H Roccaro Aldo A Orfao Alberto A Martinez-Lopez Joaquin J Rosiñol Laura L Lahuerta Juan-José JJ Blade Joan J Mateos Maria-Victoria MV San-Miguel Jesús F JF Martinez Climent Jose-Angel JA Paiva Bruno B

Nature communications 20230920 1

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 multi ...[more]

PMID: 37730678

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Project description:AimsThere are limited data examining the role of immune checkpoint (IC) ligands in the pathophysiology of heart failure (HF). Therefore, we explore this in three HF animal models and in three different human cohorts (healthy, stable, and worsening HF).Methods and resultsTranscriptomic analyses of cardiac tissue of three different HF mouse models revealed differentially expressed IC receptors and their ligands compared with control mice. Based on this observation, serum levels of three well-known IC ligands (i.e. sPD-L1, sPD-L2 and galectin-9) were measured in stable HF patients from the Vitamin D Chronic Heart Failure (VitD-CHF) study (n = 101), as well as healthy individuals from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study (n = 58). sPD-L1, sPD-L2, and galectin-9 were all associated with New York Heart Association classification. In multivariate linear regression analyses, all three IC ligands were associated with galectin-3 (β = 0.230, β = 0.283, and β = 0.304, respectively). sPD-L1 and galectin-9 were also associated with hs-troponin-T (β = 0.386 and β = 0.314). Regarding prognosis, higher serum levels of sPD-L1 and galectin-9 were significantly associated with increased risk for HF hospitalization and all-cause mortality [hazard ratio 1.69 (1.09-2.59) and hazard ratio 1.50 (1.06-2.12)]. Furthermore, the importance of IC ligands was tested in another stage of HF, namely worsening HF patients. In the worsening HF cohort (The BIOlogy Study to Tailored Treatment in Chronic Heart Failure) (n = 2032), sPD-L2 and galectin-9 were associated with New York Heart Association classification and significantly predicted outcome with an increased relative risk of 15% and 20%, after multivariable adjustment, respectively.ConclusionsIC ligands are expressed in cardiac disease models, and serum levels of IC ligands are elevated in HF patients, are associated with disease severity, and significantly predict prognosis. These data indicate a potential role for IC ligands in HF pathogenesis.

Project description:BackgroundMultiple myeloma (MM) is a hematological malignancy characterized by the abnormal proliferation of plasma cells. Mitochondrial dysfunction and dysregulated programmed cell death (PCD) pathways have been implicated in MM pathogenesis. However, the precise roles of mitochondria-related genes (MRGs) and PCD-related genes (PCDRGs) in MM prognosis remain unclear.MethodsTranscriptomic data from MM patients and healthy controls were analyzed to identify differentially expressed genes (DEGs). Candidate genes were selected by intersecting DEGs with curated lists of MRGs and PCDRGs. Univariate Cox, least absolute shrinkage and selection operator (LASSO), multivariate Cox, and stepwise regression analyses identified prognostic genes among the candidates. A risk model was constructed from these genes, and patients were stratified into high- and low-risk groups for survival analysis. Independent prognostic factors were incorporated into a nomogram to predict MM patient outcomes. Model performance was evaluated using calibration curves, receiver operating characteristic (ROC) analysis, and decision curve analysis (DCA). Finally, associations between prognostic genes and immune cell infiltration/drug responses were explored.Results2,192 DEGs were detected between MM and control samples. 30 candidate genes were identified at the intersection of DEGs, 1,136 MRGs, and 1,548 PCDRGs. TRIAP1, TOMM7, PINK1, CHCHD10, PPIF, BCL2L1, and NDUFA13 were selected as prognostic genes. The risk model stratified patients into high- and low-risk groups with significantly different survival probabilities. Age, gender, ISS stage, and risk score were independent prognostic factors. The nomogram displayed good calibration and discriminative ability (AUC) in predicting survival, with clinical utility demonstrated by DCA. 9 immune cell types showed differential infiltration between MM and controls, with significant associations to risk scores and specific prognostic genes. 57 drugs, including nelarabine and vorinostat, were predicted to interact with the prognostic genes. Ultimately, qPCR in clinical samples from MM patients and healthy donors validated the expression levels of the seven key prognostic genes, corroborating the bioinformatic findings.ConclusionSeven genes (TRIAP1, TOMM7, PINK1, CHCHD10, PPIF, BCL2L1, NDUFA13) involved in mitochondrial function and PCD pathways were identified as prognostic markers in MM. These findings provide insights into MM biology and prognosis, highlighting potential therapeutic targets.

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

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

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