Mature T-cell Research Articles

Hepatosplenic T-cell lymphoma in children and adolescents.

Hepatosplenic T-cell lymphoma (HSTCL) is an aggressive mature T-cell lymphoma characterized by significant hepatosplenomegaly, bone marrow involvement, and minimal or no lymphadenopathy. Primarily affecting young adults, it is exceptionally rare in children and adolescents. This makes diagnosis and treatment particularly challenging for pathologists and pediatric oncologists. Diagnosis typically relies on bone marrow, spleen, or liver biopsy, with histopathological features including small/medium lymphoid cells with irregular nuclear contours that obstruct the sinuses or sinusoids of the spleen or liver. Immunophenotyping usually reveals CD2/3/7 positivity and CD4/8 negativity, with γδ T-cell receptor rearrangements in most cases. Some genetic distinctions described in pediatric and adolescent patients include chromosome 7 and 8 abnormalities and mutations involving SETD2 and STAT5B. Given the lack of standardized approaches, childhood and adolescent patients with HSTCL are often treated with adult protocols, such as intensive cytotoxic chemotherapy regimens followed by allogeneic hematopoietic stem cell transplantation (HSCT). Despite these highly intensive treatments, prognosis for HSTCL remains poor in children and adolescents, with an estimated five-year overall survival of <15%. HSTCL's rarity in children and adolescents limits accurate epidemiologic estimates, clinical experience, data collection, treatment advances, and surveillance recommendations. Data on relapsed/refractory disease is even more limited. This review summarizes known clinical and histopathologic features as well as outcomes specific to children and adolescents with HSTCL, highlighting potential distinctions from adults. We will also discuss future strategies to acquire additional biologic and molecular data, streamline diagnosis, and advance treatment approaches to ultimately improve outcomes for young patients with this deadly disease.

Peripheral T-Cell Lymphoma-NOS in Children and Adolescents: a Review from the Children's Oncology Group NHL Committee.

Peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS) is a rare mature T-cell non-Hodgkin lymphoma (NHL) seen in both children and adults. While it is the most common non-anaplastic mature T-cell lymphoma of childhood, it is quite rare and therefore, the standard of care remains largely undefined. It is a disease characterized by clinical and pathological heterogeneity and is generally associated with an aggressive clinical course and poor prognosis in adults. Retrospective reports on treatment outcomes for pediatric PTCL-NOS are limited by small cohorts, variable clinical presentations, and heterogeneous treatment regimens. Though published survival rates in children appear encouraging compared to those from prospective studies in adults, the prognosis is guarded, and relatively low curative outcomes are in stark contrast to more common pediatric NHL. While recent landmark gene profiling studies have shed light on the molecular landscape of the disease in adults-identifying molecular subgroups with prognostic significance-the biology of PTCL-NOS remains unclear in children. Here we review the clinical presentation and diagnosis, historical treatment approaches, current knowledge of the disease biology and the role of hematopoietic stem cell transplant (HSCT) in PTCL-NOS in children to pursue a better understanding of this heterogenous condition and empower physicians to use this information to best support our pediatric population. Studies focusing on pediatric PTCL-NOS are required to unravel the disease biology in children, improve risk stratification, and better define upfront treatment through the role of targeted agents and HSCT, as we look to future directions of the care of children with PTCL-NOS.

The Diagnostic Utility of TRBC1 Immunohistochemistry in Mature T-Cell Lymphomas

The Diagnostic Utility of TRBC1 Immunohistochemistry in Mature T-Cell Lymphomas

Viral and Fungal Infections Early After HLA-Mismatched Hematopoietic Stem Cell Transplantation Using Low-Dose Antithymocyte Globulin in High-Risk Patients With Hematological Malignancies Not in Remission.

In vivo T-cell depletion with antithymocyte globulin (ATG), especially at high-doses has been shown to be associated with increased incidence of infections after allogeneic hematopoietic stem cell transplantation (HSCT). However, it remains unclear whether ATG, even at low-doses increases the risk of posttransplant infections in the high-risk HSCT setting. We conducted a single-center retrospective study of viral and fungal infections early after transplantation, using the data from 82 patients with hematological malignancies. Among them, 42 underwent HLA-mismatched HSCT using low-dose (2.5 mg/kg n = 41, 2.0 mg/kg n = 1) thymoglobulin (ATG patients), and 40 control patients received HSCT without ATG (non-ATG patients) during the same period. Cord blood transplantation patients were excluded. All ATG patients had hematological malignancies not in remission at the time of transplantation, and were considered to be at high-risk for posttransplant infections. There were no appreciable between-group differences in the incidence of clinically significant cytomegalovirus infection (csCMVi), late-onset CMV reactivation after discontinuation of letermovir, invasive fungal diseases or Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disease. Peak values of CMV antigenemia were almost equal in ATG and non-ATG patients. The prevention of csCMVi with letermovir was constant in the 2 groups. However, ATG patients showed earlier reactivation of CMV and higher incidence of EBV viremia than non-ATG patients. Among their underlying diseases, mature T-cell neoplasm was a significant risk factor for CMV/EBV reactivation. The use of low-dose thymoglobulin in HLA-mismatched HSCT for nonremission hematological malignancies is a reasonable strategy under careful monitoring for viral reactivation.

Angioimmunoblastic T-cell lymphoma harboring a t(8;14)(q24;q11.2)/TCR::MYC translocation that presented with intestinal infiltration.

Although rearrangement of the MYC oncogene (MYC-R) is frequently observed in aggressive B-cell lymphomas, it is extremely rare in T-cell malignancies. A 64-year-old man who had been under observation for several years because of asymptomatic pulmonary extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALToma) was admitted to our hospital because of poor general condition and hypotension. Blood tests revealed thrombocytopenia and elevated serum lactate dehydrogenase levels, whereas computed tomography revealed systemic lymphadenopathy and splenomegaly. An inguinal lymph node biopsy precipitated a diagnosis of angioimmunoblastic T-cell lymphoma (AITL). Shortly after admission, the patient experienced spontaneous intestinal perforation and hemorrhage caused by multiple intestinal infiltrations of the AITL. Although chemotherapy was administered, the patient died several weeks after admission. A 46,XY,t(8;14)(q24;q11.2) karyotype was identified, and fluorescence in situ hybridization analyses showed split signals for the MYC and T-cell receptor (TCR) alpha genes, by which a TCR::MYC translocation was confirmed. Pathological autopsy analysis revealed systemic infiltration of the AITL and no MALToma lesions. Only a few cases of mature T-cell lymphoma harboring MYC-R have been reported in the literature thus far. To the best of our knowledge, this is the first reported case of AITL with TCR::MYC rearrangement. This condition could be associated with refractoriness to chemotherapy and aggressive clinical course with systemic infiltration that included the intestine.

Development of a recombinant human IgG1 monoclonal antibody against the TRBV5-1 segment of the T cell receptor for the treatment of mature T cell neoplasms.

Mature T-cell neoplasms arise from the neoplastic transformation of a single T lymphocyte, and all cells in a neoplastic clone share the same V segment in the beta chain of the T-cell receptor (TCR). These segments may represent an innovative target for the development of targeted therapies. A specific V segment of the TCR beta chain (TRBV5-1) was analyzed using bioinformatic tools, identifying three potential antigenic peptides. One of these peptides, selected for synthesis, was used to screen a library of human single-chain variable fragments (scFv) through phage display. One fragment demonstrated high affinity and specificity for the antigen and was used to produce a human monoclonal antibody of the IgG1 class. Surface plasmon resonance (SPR) studies confirmed the high affinity of the monoclonal antibody for the antigen in the nanomolar range. Flow cytometry analysis on patients' samples demonstrated that the antibody, conjugated with a fluorochrome, selectively binds to tumor T lymphocytes expressing TRBV5-1, without binding to other lymphocytes or blood cell components. The development of fully human IgG1 monoclonal antibodies targeting specific V segments of the TCR beta chain represents a potential therapeutic option for patients with mature T-cell neoplasms.

Advances in peripheral Tcell lymphomas: pathogenesis, genetic landscapes and emerging therapeutic targets.

Peripheral Tcell lymphomas (PTCLs) are a biologically diverse and aggressive group of non-Hodgkin lymphomas that originate from mature Tcells, often presenting with complex clinical and morphological features. This review explores the challenges in diagnosing and classifying PTCLs, focusing on the intricate biology of the more common nodal entities. Advances in molecular diagnostics, such as mutational and gene expression profiling, have improved our understanding. However, the rarity and morphological variability of PTCLs continue to complicate the definition of biologically and clinically meaningful entities, as well as the application of current diagnoses in daily practice; these advancements have not yet translated into improved clinical outcomes. Standard therapies fail in most cases and lead to poor prognoses, highlighting the urgent need for improved therapeutic strategies. Precise characterisation of PTCL advances refined classification and supports the development of more targeted and effective treatments. Recent approaches have focused on biology-based risk stratification, either within specific entities or in an entity-agnostic manner. This development aims for improved treatment selection or even personalised treatment based on genetic, epigenetic and functional profiles.

Perspectives on the Mature T-Cell Lymphomas in the Middle East: A Comprehensive Review of the Present Status.

Background: T-cell lymphomas (TCLs) are rare and aggressive malignancies associated with poor outcomes, often because of the development of acquired drug resistance as well as intolerance to the established and often toxic chemotherapy regimens in elderly and frail patients. The many subtypes of TCL are well established to exhibit marked geographic variation. The epidemiology, clinical presentation, diagnosis, prognosis, and treatment of TCLs in the Middle East (ME) are yet to be explored; hence, limited data are available about these entities in this part of the world. Aim: Therefore, in this review article, we aim to discuss the available data regarding the T-cell neoplasms in the ME, including the incidence of specific subtypes of peripheral T-cell lymphoma (PTCL), as well as the trends in survival and treatment, all in an effort to understand the natural history of these complex entities across the ME.

Comprehensive genomic analysis reveals molecular heterogeneity in pediatric ALK-positive anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL) is a mature T-cell lymphoma that accounts for 10-15% of childhood lymphomas. Despite the observation that more than 90% of pediatric cases harbor the anaplastic lymphoma kinase (ALK) rearrangement resulting in aberrant ALK kinase expression, there is significant clinical, morphologic, and biological heterogeneity. To gain insights into the genomic aberrations and molecular heterogeneity within ALK-positive ALCL (ALK+ ALCL), we analyzed 46 pediatric ALK+ ALCLs by whole-exome sequencing, RNA sequencing, and DNA methylation profiling. Whole-exome sequencing found on average 25 SNV/Indel events per sample with recurring genetic events in regulators of DNA damage (TP53, MDM4), transcription (JUNB), and epigenetic regulators (TET1, KMT2B, KMT2A, KMT2C, KMT2E). Gene expression and methylation profiling consistently subclassified ALK+ ALCLs into two groups characterized by differential ALK expression levels. The ALK-low group showed enrichment of pathways associated with immune response, cytokine signaling, and a hypermethylated predominant pattern compared to the ALK-high group, which had more frequent copy number changes and was enriched with pathways associated with cell growth, proliferation, and metabolism. Altogether, these findings suggest that there is molecular heterogeneity within pediatric ALK+ ALCL, predicting distinct biological mechanisms that may provide novel insights into disease pathogenesis and represent prognostic markers.

Haematogenous seeding in mycosis fungoides and Sézary syndrome: Current evidence and clinical implications.

Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of diseases characterised by abnormal neoplastic T-cell growth in the skin. Mycosis fungoides (MF), the most common CTCL, manifests as erythematous skin patches and/or plaques, tumours or erythroderma. The disease may involve blood, lymph nodes and rarely viscera. Sézary syndrome (SS) is a unique leukaemia/lymphoma syndrome related to MF, which presents with blood and skin involvement at diagnosis. The pathogenesis of MF/SS is not fully elucidated. The presence of skin lesions at distant sites underpins a hypothesis that MF/SS lesions may develop through haematogenous seeding. Phenotypic similarities between malignant and normal T-cells led to the notion that disease-initiating mutations occur in specific subtypes of mature T-cells, which are responsible for most CTCLs. However, this mature T-cell precursor model is not always consistent with clinical observations and research on MF/SS pathogenesis. Here, we review evidence supporting an alternative model of pathogenesis for MF/SS involving haematogenous seeding as a key process responsible for the initiation and progression of the disease. According to this hypothesis, malignant transformation occurs at an early stage of T-cell development (probably in bone marrow or thymus), yielding circulating neoplastic T-cells which colonise the skin where the microenvironment is most permissive for proliferation and evolution. These mutated precursor cells seed the skin where they find a suitable niche to develop into clinically perceptible disease. Subsequently, malignant T-cells can re-enter the bloodstream, re-seed pre-existing lesions and seed new areas of the skin, causing synchronous and convergent changes in the transcriptomic profile of lesions and tumours, and clinical disease progression - 'consecutive haematogenous seeding' captures this temporal phenomenon. This model radically changes the current understanding of CTCL pathogenesis, transforming it from a primarily cutaneous disease with secondary involvement of blood, to a systemic disease, where the spread of malignant cells through the blood to the skin is not a phenomenon of advanced disease but is an essential component of pathogenesis. This understanding of MF/SS could have several clinical implications, including standardising our approach to assessing blood tumour burden, potential advances in prognosis and monitoring, and investigating combination treatments to improve patient outcomes.

Global outcomes and prognosis for relapsed/refractory mature T-cell and NK-cell lymphomas: results from the PETAL consortium

AbstractVariances in global access to drugs and treatment practices make it challenging to understand the benefit of contemporary therapies in patients with relapsed and refractory (R/R) mature T-cell and natural killer–cell lymphomas (MTCL and MNKCL). We conducted an international retrospective cohort study of 925 patients with R/R MTCL and MNKCL. In peripheral T-cell lymphoma–not otherwise specified and anaplastic lymphoma kinase–negative anaplastic large cell lymphoma (ALK– ALCL), patients with relapsed lymphoma demonstrated a superior median overall survival (OS) relative to refractory from the time of second-line treatment. We identified several independent predictors of OS for R/R lymphoma including age >60 years, primary refractory disease, histological subtype other than angioimmunoblastic T-cell lymphoma (AITL), extranodal sites >1, Ki67 ≥40%, and absolute lymphocyte count less than the lower limit of normal. A multivariable model incorporating these formed the basis for a prognostic index for R/R TCL, in which patients are stratified into low-risk (0-1 risk factor), intermediate-risk (2-3 risk factors), or high-risk (≥4 risk factors) groups, which were associated with 3-year OS of 57.14%, 23.3%, and 7%, respectively. Patients received either a "novel" single agent (SA; 35%) or cytotoxic chemotherapy (CC; 60%) for their second-line treatment. Higher progression-free survival was observed with SA over CC for the entire cohort with a higher 3-year OS in AITL and ALK– ALCL. Among the SA, small-molecule inhibitors demonstrated OS advantage relative to CC in AITL. Our results highlight continued efficacy of novel drugs globally and the potential of a new prediction model in informing heterogeneous prognosis within the R/R population of MTCL and MNKCL.

T-Cell Phenotypes and Systemic Cytokine Profiles of People Living with HIV Admitted to Hospital with COVID-19.

Whether SARS-CoV-2 infection leads to a higher mortality and morbidity in people living with HIV (PLWH) in Africa remains inconclusive. In this study, we explored the differences in the T-cell phenotypes between people with and without HIV on the day of admission (V1) and ±7 days later (V2), as well as their cytokine/chemokine profiles on V1. Patients admitted with COVID-19 were recruited between May 2020 and December 2021 from the Steve Biko Academic and Tshwane District Hospitals in Pretoria, South Africa. Of 174 patients, 37 (21%) were PLWH. T-cell profiles were determined by flow cytometry, and cytokine levels were determined using a multiplex suspension bead array. PLWH were significantly younger than those without HIV, and were more likely to be female. In an adjusted analysis, PLWH had higher percentages of CD4+ central memory (CM) programmed cell death protein 1 (PD-1)+, CD8+ effector memory (EM)2, and CD8+ EM4 CD57+ cells, as well as higher concentrations of interleukin (IL)-35 at admission. PLWH with CD4+ T-cell counts of >200 cells/mm3 had altered CD4+ and CD8+ T-cell profiles, lower levels of systemic inflammation measured by plasma ferritin and PCT levels, and less severe disease. PLWH with CD4+ T-cell counts of <200 cells/mm3 on admission had higher concentrations of IL-6 and lower levels of IL-29. At V2, the percentages of CD4+ CM PD-1+ T-cells and CD8+ EM4 T-cells co-expressing CD57 and PD-1 remained higher in PLWH, while all other CD8+ EM populations were lower. Fewer CD8+ EM T-cells after ±7 days of admission may be indicative of mechanisms inhibiting EM T-cell survival, as indicated by the higher expression of IL-35 and the T-cell maturation arrest observed in PLWH. This profile was not observed in PLWH with severe immunodeficiency, highlighting the need for differentiated care in the broader PLWH population.

Integrative transcriptomic profiling uncovers immune and functional responses to bisphenol a across multiple tissues in male mice

ABSTRACT Bisphenol A (BPA), an endocrine-disrupting substance commonly found in plastics and receipts, is associated with adverse effects, including endocrine disorders, reduced fertility, and metabolic issues. To gain insights into its effects on biological systems, we observed the adverse effects of BPA in male Institute of Cancer Research (ICR) mice exposed to BPA at the lowest observed adverse effect level for 6 weeks, in comparison with the control groups. We constructed a comprehensive transcriptome profile using 20 different tissues to analyze the changes in the whole-body systems. This involved employing differential gene expression, tissue-specific gene, and gene co-expression network analyses. The study revealed that BPA exposure led to significant differences in the transcriptome in the thymus, suggesting activation of T-cell differentiation and maturation in response to BPA treatment. Furthermore, various tissues exhibited immune response activation, potentially due to the migration of immune cells from the thymus. BPA exposure also caused immune-related functional changes in the colon, liver, and kidney, as well as abnormal signaling responses in the sperm. The transcriptome analysis serves as a valuable resource for understanding the functional impact of BPA, providing profound insights into the effects of BPA exposure and emphasizing the need for further research on potential associated health risks.

Transcription factor TCF1 binds to RORγt and orchestrates a regulatory network that determines homeostatic Th17 cell state

T helper (Th) 17 cells encompass a spectrum of cell states, including cells that maintain homeostatic tissue functions and pro-inflammatory cells that can drive autoimmune tissue damage. Identifying regulators that determine Th17 cell states can identify ways to control tissue inflammation and restore homeostasis. Here, we found that interleukin (IL)-23, a cytokine critical for inducing pro-inflammatory Th17 cells, decreased transcription factor Tcell factor 1 (TCF1) expression. Conditional deletion of TCF1 in mature Tcells increased the pro-inflammatory potential of Th17 cells, even in the absence of IL-23 receptor signaling, and conferred pro-inflammatory potential to homeostatic Th17 cells. Conversely, sustained TCF1 expression decreased pro-inflammatory Th17 potential. Mechanistically, TCF1 bound to RORγt, thereby interfering with its pro-inflammatory functions, and orchestrated a regulatory network that determined Th17 cell state. Our findings identify TCF1 as a major determinant of Th17 cell state and provide important insight for the development of therapies for Th17-driven inflammatory diseases.

Advancing Diagnostic Accuracy and Quality of Patient Care Through the Implementation of a Flow Cytometry Quality Assurance Program

Abstract Introduction/Objective Flow cytometry immunophenotypic analysis plays an important role in the diagnosis, classification and disease monitoring of hematological neoplasms. However, interpretation of flow cytometry testing can be challenging, especially when using highly complex antibody panels. Thus exploring ways to improve diagnostic accuracy and in turn improving quality of patient care is needed. Methods/Case Report A flow cytometry quality assurance (QA) program was developed. Cases from various complex flow cytometry panels were randomly selected and cross-reviewed by a second pathologist on a daily basis. The outcomes of the QA review were categorized into three groups: complete agreement, minor discrepancy and major discrepancy. Each discrepancy, once identified, underwent a process of documentation, discussion and resolution. The reports were then modified in a timely manner and the clinical teams were notified of the changes. Recurrent issues and common pitfalls were reviewed and discussed at a weekly QA meeting. Here we summarize our 3-years’ experience with this program. Results (if a Case Study enter NA) In total, 6,166 cases were evaluated by the QA program; 6,028 (97.7%) cases showed complete concordance, 120 (2.0%) cases showed minor discrepancies and 18 (0.3%) cases showed major discrepancies. Antibody panels designed to evaluate mature and immature T-cell abnormalities showed the highest rate of discrepancy, 2.8%, whereas panels designed for evaluation of myelodysplastic syndromes showed the lowest discrepancy rate, 1.7%. When analyzing the trends of concordance and discrepancy over time, we found a statistically significant decrease in discrepancies over time, from 4% at the beginning of the QA program to 1.5% in the most recent time interval. Conclusion The overall concordance rate was 97.7%. The remaining 2.3% cases showed discrepancies that required a correction, underscoring the value and necessity of having a QA program. The overall discrepancy rates exhibited a gradual decline over time, indicative of the positive impact of the QA program on enhancing diagnostic competency and accuracy over time.

ALK-positive Anaplastic Large Cell Lymphoma Involving the Spinal Cord

Abstract Introduction/Objective ALK-positive anaplastic large cell lymphoma (ALCL) is a mature T-cell lymphoma that accounts for approximately 3% of non-Hodgkin lymphoma cases in the adult population. Lymph node involvement is most commonly seen, followed by extra-nodal involvement of the skin, soft tissue, and bone. Central nervous system involvement is rare at the time of diagnosis. This case study features a patient with systemic ALK-positive ALCL involving multiple nodal and extra-nodal sites, most notably the spinal cord. Methods/Case Report A 22-year-old female presented to the hospital with worsening back pain accompanied by neurological symptoms. MRI scans of her spine revealed extensive patchy abnormal marrow signal with enhancement of the thoracolumbar vertebrae (T1-L2) and adjacent extension into the spinal canal (T3-T7, T10-L1, L3-S1) and paraspinal soft tissues. A laminectomy of the T5-T7 and T11-T12 levels was performed for surgical decompression, and epidural and paraspinal resection specimens were submitted. These specimens, along with an excisional axillary lymph node biopsy, demonstrated ALK-positive ALCL after comprehensive immunohistochemical studies. In-situ hybridization for EBV was negative. CHOP therapy was initiated, but treatment was complicated by Candidemia and disseminated intravascular coagulation. The patient rapidly declined and passed away less than a month after hospital admission. At autopsy, enlargement of lymph nodes, the left ovary (17.8 g), and spleen (383.6 g) were noted on gross examination. A solid, white-tan lesion (2.1 x 0.9 x 0.8 cm) was found in the left ovary. Necrosis and infiltrates of large, pleomorphic lymphoid cells with irregular nuclear contours and prominent nucleoli were seen on microscopic examination of the spinal cord and leptomeninges, vertebral bone marrow, mediastinal lymph nodes, spleen, and left ovary. Consistent with previously submitted surgical specimens, the viable neoplastic cells stained strongly positive for ALK-1, CD4, and CD30. Results (if a Case Study enter NA) NA Conclusion This case study highlights an atypical presentation of ALCL with a fatal outcome. Given the availability of effective treatment options, prompt diagnosis is crucial to improving survival outcomes. Additional research is necessary to elucidate the clinical and pathological features of ALCL. The differential for back pain is broad, but including this entity for patients with similarly insidious clinical presentations can prevent a delay in diagnosis that allows for rapid progression of disease.

Prevalence and Prognostication of CD5+ Mature T-Cell Lymphomas

Background: T-cell lymphomas (TCLs) are a group of heterogenous cancers with poor rates and duration of response. There remains a great challenge in risk stratification of these cancers. Cluster of differentiation (CD) 5 has shown prognostic implication in many subtypes of B-cell lymphoma; however, its role in TCLs is not known. Methods: We performed a single-institution retrospective analysis of newly diagnosed patients with TCL. CD5 positivity was determined based on positive results via immunohistochemistry and/or flow cytometry. We used univariate and multivariable analysis of biological factors to assess their association with survival outcomes. Results: A total of 194 patients with TCL spanning 14 subtypes were identified. CD5 positivity was noted in 63% of patients, with the highest proportion of CD5 expression in TFH TCL (93.9%), PTCL-NOS (82.9%), and ATLL (77.8%) (p = 0.00004). Older age at diagnosis (p = 0.001), stage III or IV disease (p = 0.05), and bone marrow involvement (p = 0.003) were also associated with CD5 expression. Complete response rates were numerically lower in patients with CD5+ TCL across all subtypes. OS/PFS was not statistically associated with CD5 status in the overall cohort; however there was significantly decreased OS in CD5+ TFH TCL (p = 0.04) and CD5+ ATLL (p = 0.04) patients. Conclusions: This study represents the first to examine CD5 expression as a prognostic biomarker for outcomes in TCL. The frequent expression of CD5 in the most common nodal TCL in the Western world underpins its potential as an attractive target for cellular therapies. Confirmation of these findings in a larger cohort and investigation of potential pathophysiological mechanisms explaining our observations are planned.

Microsurgical assessment of thymus vascular anatomy

BackgroundThe thymus is pivotal for immune system development by facilitating T-cell maturation. Current treatments for congenital athymia typically involve avascular transplantation of allogeneic thymic tissue. However, vascularizing an infant thymus for transplantation could offer improved outcomes, necessitating a detailed understanding of its vascular anatomy. MethodBetween June and November 2022, we conducted a feasibility study at our tertiary care university hospital, examining seven thymus glands that were surgically removed and discarded during corrective surgeries for congenital heart disease in patients aged 16 days to 17 months. ResultsAngiographic analysis revealed distinct vascular pathways in infant thymic lobes, with arteries averaging 0.5 mm and veins 0.8 mm in diameter, both showing adequate perfusion with Belzer solution. ConclusionThese findings provide critical insights into the vascular anatomy of the infant thymus, underscoring its potential for microvascular revascularization and transplantation.

Generation of ex vivo autologous hematopoietic stem cell-derived T lymphocytes for cancer immunotherapy

CD19CAR-T cell therapy demonstrated promising outcomes in relapsed/refractory B-cell malignancies. Nonetheless, the limited T-cell function and ineffective T-cell apheresis for therapeutic purposes are still concern in heavily pretreated patients. We investigated the feasibility of generating hematopoietic stem cell-derived T lymphocytes (HSC-T) for cancer immunotherapy. The patients’ autologous peripheral blood HSCs were enriched for CD34+ and CD3+ cells. The CD34+ cells were then cultured following three steps of lymphoid progenitor differentiation, T-cell differentiation, and T-cell maturation processes. HSC-T cells were successfully generated with robust fold expansion of 3735 times. After lymphoid progenitor differentiation, CD5+ and CD7+ cells remarkably increased (65–84 %) while CD34+ cells consequentially declined. The mature CD3+ cells were detected up to 40 % and 90 % on days 42 and 52, respectively. The majority of HSC-T population was naïve phenotype compared to CD3-T cells (73 % vs 34 %) and CD8:CD4 ratio was 2:1. The higher level of cytokine and cytotoxic granule secretion in HSC-T was observed after activation. HSC-T cells were assessed for clinical application and found that CD19CAR-transduced HSC-T cells demonstrated higher cytokine secretion and a trend of superior cytotoxicity against CD19+ target cells compared to control CAR-T cells. A chronic antigen stimulation assay revealed similar T-cell proliferation, stemness, and exhaustion phenotypes among CAR-T cell types. In conclusions, autologous HSC-T was feasible to generate with preserved T-cell efficacy. The HSC-T cells are potentially utilized as an alternative option for cellular immunotherapy.

Intron retention as an excellent marker for diagnosing depression and for discovering new potential pathways for drug intervention.

Peripheral inflammation is often associated with depressive disorders, and immunological biomarkers of depression remain a focus of investigation. We performed RNA-seq analysis of RNA transcripts of human peripheral blood mononuclear cells from a case-control study including subjects with self-reported depression in the pre-symptomatic state of major depressive disorder and analyzed differentially expressed genes (DEGs) and the frequency of intron retention (IR) using rMATS. Among the statistically significant DEGs identified, the 651 upregulated DEGs were particularly enriched in the term "bacterial infection and phagocytosis", whereas the 820 downregulated DEGs were enriched in the terms "antigen presentation" and "T-cell proliferation and maturation". We also analyzed 158 genes for which the IR was increased (IncIR) and 211 genes for which the IR was decreased (DecIR) in the depressed subjects. Although the Gene Ontology terms associated with IncIR and DecIR were very similar to those of the up- and downregulated genes, respectively, IR genes appeared to be particularly enriched in genes with sensor functions, with a preponderance of the term "ciliary assembly and function". The observation that IR genes specifically interact with innate immunity genes suggests that immune-related genes, as well as cilia-related genes, may be excellent markers of depression. Re-analysis of previously published RNA-seq data from patients with MDD showed that common IR genes, particularly our predicted immune- and cilia-related genes, are commonly detected in populations with different levels of depression, providing validity for using IR to detect depression. Depression was found to be associated with activation of the innate immune response and relative inactivation of T-cell signaling. The DEGs we identified reflect physiological demands that are controlled at the transcriptional level, whereas the IR results reflect a more direct mechanism for monitoring protein homeostasis. Accordingly, an alteration in IR, namely IncIR or DecIR, is a stress response, and intron-retained transcripts are sensors of the physiological state of the cytoplasm. The results demonstrate the potential of relative IR as a biomarker for the immunological stratification of depressed patients and the utility of IR for the discovery of novel pathways involved in recovery from depression.