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

Large T cell; Immune checkpoints; Multiple myelomaCèl·lules T grans; Punts de control immunitari; Mieloma múltipleCélulas T grandes; Puntos de control inmunitario; Mieloma múltipleTumor 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

Predicting long-term disease control in transplant-ineligible patients with multiple myeloma: impact of an MGUS-like signature

Disease control; Multiple myeloma; BiomarkersControl de la malaltia; Mieloma múltiple; BiomarcadorsControl de la enfermedad; Mieloma múltiple; BiomarcadoresDisease control at 5 years would be a desirable endpoint for elderly multiple myeloma (MM) patients, but biomarkers predicting this are not defined. Therefore, to gain further insights in this endpoint, a population of 498 newly diagnosed transplant-ineligible patients enrolled in two Spanish trials (GEM2005MAS65 and GEM2010MAS65), has been analyzed. Among the 435 patients included in this post-hoc study, 18.6% remained alive and progression free after 5 years of treatment initiation. In these patients, overall survival (OS) rate at 10 years was 60.8% as compared with 11.8% for those progressing within the first 5 years. Hemoglobin (Hb) ≥ 12 g/dl (OR 2.74, p = 0.001) and MGUS-like profile (OR 4.18, p = 0.005) were the two baseline variables associated with long-term disease-free survival. Upon including depth of response (and MRD), Hb ≥ 12 g/dl (OR 2.27) and MGUS-like signature (OR 7.48) retained their predictive value along with MRD negativity (OR 5.18). This study shows that despite the use of novel agents, the probability of disease control at 5 years is still restricted to a small fraction (18.6%) of elderly MM patients. Since this endpoint is associated with higher rates of OS, this study provides important information about diagnostic and post-treatment biomarkers helpful in predicting the likelihood of disease control at 5 years

Role of light chain clearance in the recovery of renal function in multiple myeloma: another point of view

Acute kidney injury; Hemodialysis; Multiple myelomaLesió renal aguda; Hemodiàlisi; Mieloma múltipleLesión renal aguda; Hemodiálisis; Mieloma múltipleBackground Acute kidney injury (AKI) in patients with multiple myeloma (MM) requiring renal replacement treatment (RRT) is associated with high morbidity and mortality. Early reduction of serum free light chains (FLC) using both targeted therapy against MM and intensive hemodialysis (IHD) may improve renal outcomes. We evaluated the effectiveness of two different RRT techniques on renal recovery in an MM patient population: standard dialysis procedure vs IHD with either polymethylmethacrylate (PMMA) or hemodiafiltration with endogenous reinfusion (HFR). Methods This was a multicentric retrospective study with severe AKI related to MM, between 2011 and 2018. Twenty-five consecutive patients with AKI secondary to MM requiring RRT were included. Patients that underwent IHD received six dialysis sessions per week during the first 14 days (PMMA vs HFR). All patients were diagnosed with de novo MM or first relapsed MM. Primary outcome was renal recovery defined as dialysis-free at 6 months follow-up. Results A total of 25 patients were included. Seventeen patients received IHD and eight standard dialysis. All patients were treated with targeted therapy, 84% bortezomib-based. Of the 25 patients included, 14 (56%) became dialysis independent. We observed a higher proportion of patients who received IHD in the group who recovered kidney function compared with those who remained in HD (92.9% vs 36.4%, P = .007). In our study, the use of IHD to remove FLC had a statistically significant association with renal recovery compared with the standard dialysis group (P = .024). Conclusion Early reduction of FLC with IHD as an adjuvant treatment along with MM-targeted therapy may exert a positive impact on renal recovery

Evaluation of alpha 1-antitrypsin and the levels of mRNA expression of matrix metalloproteinase 7, urokinase type plasminogen activator receptor and COX-2 for the diagnosis of colorectal cancer

Background Colorectal cancer (CRC) is the second most common cause of death from cancer in both men and women in the majority of developed countries. Molecular tests of blood could potentially provide this ideal screening tool. Aim Our objective was to assess the usefulness of serum markers and mRNA expression levels in the diagnosis of CRC. Methods In a prospective study, we measured mRNA expression levels of 13 markers (carbonic anhydrase, guanylyl cyclase C, plasminogen activator inhibitor, matrix metalloproteinase 7 (MMP7), urokinase-type plasminogen activator receptor (uPAR), urokinase-type plasminogen activator, survivin, tetranectin, vascular endothelial growth factor (VEGF), cytokeratin 20, thymidylate synthase, cyclooxygenase 2 (COX-2), and CD44) and three proteins in serum (alpha 1 antitrypsin, carcinoembryonic antigen (CEA) and activated C3 in 42 patients with CRC and 33 with normal colonoscopy results. Results Alpha 1-antitrypsin was the serum marker that was most useful for CRC diagnosis (1.79±0.25 in the CRC group vs 1.27±0.25 in the control group, P<0.0005). The area under the ROC curve for alpha 1-antitrypsin was 0.88 (0.79-0.96). The mRNA expression levels of five markers were statistically different between CRC cases and controls: those for which the ROC area was over 75% were MMP7 (0.81) and tetranectin (0.80), COX-2 (0.78), uPAR (0.78) and carbonic anhydrase (0.77). The markers which identified early stage CRC (Stages I and II) were alpha 1-antitrypsin, uPAR, COX-2 and MMP7. Conclusions Serum alpha 1-antitrypsin and the levels of mRNA expression of MMP7, COX-2 and uPAR have good diagnostic accuracy for CRC, even in the early stages

Angular moments of the decay Λb 0 → Λμ + μ − at low hadronic recoil

An analysis of the angular distribution of the decay Λ0 b → Λµ +µ − is presented, using data collected with the LHCb detector between 2011 and 2016 and corresponding to an integrated luminosity of approximately 5 fb−1 . Angular observables are determined using a moment analysis of the angular distribution at low hadronic recoil, corresponding to the dimuon invariant mass squared range 15 < q2 < 20 GeV2/c4 . The full basis of observables is measured for the first time. The lepton-side, hadron-side and combined forward-backward asymmetries of the decay are determined to b

Measurement of Z → τ + τ − production in proton-proton collisions at √s=8 TeV

A measurement of Z → τ +τ − production cross-section is presented using data, corresponding to an integrated luminosity of 2 fb−1 , from pp collisions at √ s = 8 TeV collected by the LHCb experiment. The τ +τ − candidates are reconstructed in final states with the first tau lepton decaying leptonically, and the second decaying either leptonically or to one or three charged hadrons. The production cross-section is measured for Z bosons with invariant mass between 60 and 120 GeV/c2 , which decay to tau leptons with transverse momenta greater than 20 GeV/c and pseudorapidities between 2.0 and 4.5. The crosssection is determined to be σpp→Z→τ+τ− = 95.8 ± 2.1 ± 4.6 ± 0.2 ± 1.1 pb, where the first uncertainty is statistical, the second is systematic, the third is due to the LHC beam energy uncertainty, and the fourth to the integrated luminosity uncertainty. This result is compatible with NNLO Standard model predictions. The ratio of the cross-sections for Z → τ +τ − to Z → µ +µ − (Z → e +e −), determined to be 1.01 ± 0.05 (1.02 ± 0.06), is consistent with the lepton-universality hypothesis in Z decays

Validation of miR-1228-3p as Housekeeping for MicroRNA Analysis in Liquid Biopsies from Colorectal Cancer Patients

BACKGROUND: Circulating microRNA (miRNA) analysis is a growing research field. However, it usually requires an endogenous control or housekeeping (HK) in order to normalize expression of specific miRNAs throughout different samples. Unfortunately, no adequate HK for circulating miRNA analysis is still known in the colorectal cancer (CRC) context whereas several have been suggested. Hence, our aims were to validate the previously suggested miR-1228-3p as HK for CRC studies, to compare its suitability with the widely used miR-16-5p, and to evaluate the influence of hemolysis on both miRNAs. METHODS: We analyzed by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) the expression of miR-1228-3p, miR-16-5p and the spike-in cel-miR-39 in a set of 297 plasmas (92 CRC, 101 advanced adenomas -AA-, and 100 controls) and 213 serum samples (59 CRC, 74 AA and 80 controls). We also analyzed both miRNAs depending on the hemolysis degree in 7 plasmas and 31 serums. RESULTS: Levels of miR-1228-3p and miR-16-5p did not show significant differences between groups although miR-16-5p exhibited more variability in plasma and serum samples. Importantly, the combination of cel-miR-39 and miR-1228-3p was the most stable one. Moreover, we observed that miR-16-5p was significantly influenced by hemolysis in contrast with miR-1228-3p that exhibited no correlation with this confounding factor in both biofluids. CONCLUSION: MiR-1228-3p has been validated as an adequate endogenous control for circulating miRNA analysis in CRC and AA liquid biopsies

Observation of the decay Bs0→D¯0K+K−

The first observation of the B0 s → D¯ 0KþK− decay is reported, together with the most precise branching fraction measurement of the mode B0 → D¯ 0KþK−. The results are obtained from an analysis of pp collision data corresponding to an integrated luminosity of 3.0 fb−1. The data were collected with the LHCb detector at center-of-mass energies of 7 and 8 TeV. The branching fraction of the B0 → D¯ 0KþK− decay is measured relative to that of the decay B0 → D¯ 0πþπ− to be BðB0→D¯ 0KþK−Þ BðB0→D¯ 0πþπ−Þ ¼ ð6.9 0.4 0.3Þ%, where the first uncertainty is statistical and the second is systematic. The measured branching fraction of the B0 s → D¯ 0KþK− decay mode relative to that of the corresponding B0 decay is BðB0 s→D¯ 0KþK−Þ BðB0→D¯ 0KþK−Þ ¼ ð93.0 8.9 6.9Þ%. Using the known branching fraction of B0 → D¯ 0πþπ−, the values of BðB0 →D¯ 0KþK−Þ¼ð6.10.40.30.3Þ×10−5 and BðB0 s →D¯ 0KþK−Þ¼ð5.70.50.40.5Þ×10−5 are obtained, where the third uncertainties arise from the branching fraction of the decay modes B0 → D¯ 0πþπ− and B0 → D¯ 0KþK−, respectively

Plasma MicroRNA Signature Validation for Early Detection of Colorectal Cancer

OBJECTIVES: Specific microRNA (miRNA) signatures in biological fluids can facilitate earlier detection of the tumors being then minimally invasive diagnostic biomarkers. Circulating miRNAs have also emerged as promising diagnostic biomarkers for colorectal cancer (CRC) screening. In this study, we investigated the performance of a specific signature of miRNA in plasma samples to design a robust predictive model that can distinguish healthy individuals from those with CRC or advanced adenomas (AA) diseases. METHODS: Case control study of 297 patients from 8 Spanish centers including 100 healthy individuals, 101 diagnosed with AA, and 96 CRC cases. Quantitative real-time reverse transcription was used to quantify a signature of miRNA (miRNA19a, miRNA19b, miRNA15b, miRNA29a, miRNA335, and miRNA18a) in plasma samples. Binary classifiers (Support Vector Machine [SVM] linear, SVM radial, and SVM polynomial) were built for the best predictive model. RESULTS: Area under receiving operating characteristic curve of 0.92 (95% confidence interval 0.871-0.962) was obtained retrieving a model with a sensitivity of 0.85 and specificity of 0.90, positive predictive value of 0.94, and negative predictive value of 0.76 when advanced neoplasms (CRC and AA) were compared with healthy individuals. CONCLUSIONS: We identified and validated a signature of 6 miRNAs (miRNA19a, miRNA19b, miRNA15b, miRNA29a, miRNA335, and miRNA18a) as predictors that can differentiate significantly patients with CRC and AA from those who are healthy. However, large-scale validation studies in asymptomatic screening participants should be conducted