T-cell Profiles Research Articles

Systematic review and quantitative meta-analysis of age-dependent human T-lymphocyte homeostasis

ObjectiveTo evaluate and quantitatively describe age-dependent homeostasis for a broad range of total T-cells and specific T-lymphocyte subpopulations in healthy human subjects.MethodsA systematic literature review was performed to identify and collect relevant quantitative information on T-lymphocyte counts in human blood and various organs. Both individual subject and grouped (aggregated) data on T-lymphocyte observations in absolute and relative values were digitized and curated; cell phenotypes, gating strategies for flow cytometry analyses, organs from which observations were obtained, subjects’ number and age were also systematically inventoried. Age-dependent homeostasis of each T-lymphocyte subpopulation was evaluated via a weighted average calculation within pre-specified age intervals, using a piece-wise equal-effect meta-analysis methodology.ResultsIn total, 124 studies comprising 11722 unique observations from healthy subjects encompassing 20 different T-lymphocyte subpopulations – total CD45+ and CD3+ lymphocytes, as well as specific CD4+ and CD8+ naïve, recent thymic emigrants, activated, effector and various subpopulations of memory T-lymphocytes (total-memory, central-memory, effector-memory, resident-memory) – were systematically collected and included in the final database for a comprehensive analysis. Blood counts of most T-lymphocyte subpopulations demonstrate a decline with age, with a pronounced decrease within the first 10 years of life. Conversely, memory T-lymphocytes display a tendency to increase in older age groups, particularly after ~50 years of age. Notably, an increase in T-lymphocyte numbers is observed in neonates and infants (0 – 1 year of age) towards less differentiated T-lymphocyte subpopulations, while an increase into more differentiated subpopulations emerges later (1 – 5 years of age).ConclusionA comprehensive systematic review and meta-analysis of T-lymphocyte age-dependent homeostasis in healthy humans was performed, to evaluate immune T-cell profiles as a function of age and to characterize generalized estimates of T-lymphocyte counts across age groups. Our study introduces a quantitative description of the fundamental parameters characterizing the maintenance and evolution of T-cell subsets with age, based on a comprehensive integration of available organ-specific and systems-level flow cytometry datasets. Overall, it provides the most up-to-date view of physiological T-cell dynamics and its variance and may be used as a consistent reference for gaining further mechanistic understanding of the human immune status in health and disease.

P0195 Immune reconstitution following autologous hematopoietic stem cell transplantation with cyclophosphamide-free mobilization for refractory Crohn’s disease

Abstract Background Autologous hematopoietic stem cell transplantation (aHSCT) has emerged as an effective therapeutic strategy for patients with severe chronic inflammatory conditions that are refractory to conventional treatment, including Crohn’s disease. The success of aHSCT is thought to be grounded in resetting the break of immunological tolerance, but the exact mechanisms underlying a favourable response remain incompletely understood. Methods We followed the immune reconstitution of 9 patients with severe refractory Crohn’s disease from one month until more than 2 years post-aHSCT. We performed flow cytometry to follow immune cell populations and functional T cells markers over time, in addition to Olink proteomics to study the inflammatory response in serum. Results Transplantation proceeded safely, without major adverse events in any of the 9 patients. aHSCT resulted in considerable improvement of disease status in 6 patients, with 3 patients classified as non-responders. After transplantation, we observed a strong change in the peripheral T-cell subset composition, with a reduction of the CD4/CD8 ratio and a reduction of naïve over effector memory (EM) T cells. Non-responders appeared distinct by a higher CD4/CD8 ratio and higher naïve over T-EM frequencies already before transplantation, and a smaller change in subset composition after transplantation. Remarkably, the local T-cell composition did not mirror the changes in the periphery, with an increased CD4/CD8 ratio in intestinal biopsies post-aHSCT, underscoring that a more detailed study of local versus peripheral responses to aHSCT is essential in aiding our understanding of its efficacy. Functionally, the changes in the peripheral T-cell profile were minimal and not clearly related to response. Although the pro-inflammatory profile was not altered, we did find a small but significant increase in the expression of regulatory markers. Conclusion aHSCT resulted in strong changes in the T-cell subset composition of Crohn’s disease patients, but only small changes in functional markers related to inflammation, regulation and homing. Non-responders could be distinguished at baseline by a different T-cell composition and also experienced less profound changes herein upon transplantation.

Vδ2 T-cells response in people with Mpox infection: a three-month longitudinal assessment

The first evidence that Orthopoxvirus induced the expansion in vivo and the recall of effector innate Vδ2 T-cells was described in a macaque model. Although, an engagement of αβ T-cells specific response in patients infected with human monkeypox (Mpox) was demonstrated, little is known about the role of γδ T-cells during Mpox infection. IFN-γ-producing γδ T-cells in the resistance to poxviruses may a key role in inducing a protective type 1 memory immunity. We analyzed the kinetics of Vδ2 T-cell response from the acute phase up to three months after Mpox infection. Fourteen MSM subjects (5 PWH, 35.7%) were enrolled in a longitudinal study from May to July 2022. Blood samples were collected in the early phase of infection (T1, T2) and at 3 months (T3M) post-symptom onset. Vδ2 T-cell profiles (CD45RA/CCR7), activation/exhaustion markers (CD38/HLA-DR/CD57/PD-1/TIM-3), cytokine production (IFN-γ/TNF-α) and CD107a expression were assessed by multiparametric flow cytometry. Ten healthy donors (HD) were used as a control group. At T1, Vδ2 T-cell frequency of patients decreased, and effector memory Vδ2 T-cells increased with respect to HD. Activation/exhaustion markers were higher than HD. Vδ2 functionality decreased at T1 related to HD, and it was associated with CD38 and HLA-DR higher expression as well as TIM-3. Vδ2 T-cells restored their profile at T3M. The presence of effector/activated Vδ2 T-cells in the early stages of Mpox infection and their capability to activate quickly, producing pro-inflammatory cytokines, may be useful to enhance the early adaptive response to human Mpox, maintaining a protective memory/effector T-cell response.

Nivolumab to restore T-cell fitness in CAR-T refractory multiple myeloma.

Efficacy and durability remain central shortcomings of T-cell based therapies in multiple myeloma (MM). Here, we employ blood-based transcriptional T-cell profiling to define impaired T-cell fitness as putative biomarker associated with sensitivity to PD1 inhibition in CAR-T refractory MM patients.

Distinct CD8+ T-cell types Associated with COVID-19 Severity in Unvaccinated HLA-A2+ Patients.

Although emerging data have revealed the critical role of memory CD8+ T cells in preventing and controlling SARS-CoV-2 infection, virus-specific CD8+ T-cell responses against SARS-CoV-2 and its memory and innate-like subsets in unvaccinated COVID-19 patients with various disease manifestations in an HLA-restricted fashion remain to be understood. Here, we show the strong association of protective cellular immunity with mild COVID-19 and unique cell types against SARS-CoV-2 virus in an HLA-A2 restricted manner. ELISpot assays reveal that SARS-CoV-2-specific CD8+ T-cell responses in mild COVID-19 patients are significantly higher than in severe patients, whereas neutralizing antibody responses against SARS-CoV-2 virus significantly correlate with disease severity. Single-cell analyses of HLA-A2-restricted CD8+ T cells, which recognize highly conserved immunodominant SARS-CoV-2-specific epitopes, demonstrate divergent profiles in unvaccinated patients with mild versus severe disease. CD8+ T-cell types including cytotoxic KLRB1 + CD8αα cells with innate-like T-cell signatures, IFNG hi ID3 hi memory cells and IL7R + proliferative stem cell-like memory cells are preferentially observed in mild COVID-19, whereas distinct terminally-differentiated T-cell subsets are predominantly detected in severe COVID-19: highly activated FASL hi T-cell subsets and early-terminated or dysfunctional IL4R + GATA3 + stem cell-like memory T-cell subset. In conclusion, our findings suggest that unique and contrasting SARS-CoV-2-specific CD8+ T-cell profiles may dictate COVID-19 severity.

A unique inflammaging profile generated by T cells from people with obesity is metformin resistant.

The alarmingly high prevalence of obesity in older adults coupled with the negative health effects of chronic inflammation in both obesity and aging highlight the importance of studies investigating the impacts of obesity on age-related inflammation. Since shifts in peripheral T-cell metabolism and function drive systemic inflammation in both obesity and aging, we hypothesize that obesity impacts the Th17-dominated inflammaging profile we identified in lean subjects and thus modifies the anti-inflammatory effects of geroprotective drugs like metformin. New cytokine profiling data showed that CD4+ T cells from older people with obesity generate a profile that specifically excludes Th17 cytokines. Metformin failed to change the age-associated T-cell profile in obesity, despite lowering both mitochondrial respiration and reactive oxygen species (ROS) production. Metformin did not improve macroautophagy in T cells from older people with obesity, in sharp contrast to the ability of metformin to promote autophagy in T cells from older lean subjects. These data indicate that body mass index modifies the mechanisms supporting inflammaging in T cells from older subjects, and that metformin-mediated restoration of redox balance is insufficient to stem obesity-associated inflammaging. We conclude that obesity fundamentally changes the mechanisms that promote inflammaging, and thus obesity becomes a critical consideration for clinical trials of geroprotective agents such as metformin.

A multidimensional toolkit for elucidating temporal trajectories in cell development in vivo.

Progenitor cells initiate development upon receiving key signals, dynamically altering gene and protein expression to diverge into various lineages and fates. Despite the use of several experimental approaches, including the Fluorescent Timer-based method Timer-of-cell-kinetics-and-activity (Tocky), analysing time-dependent processes at the single-cell level in vivo remains challenging. This study introduces a novel integrated experimental and computational approach, using an advanced multidimensional toolkit. This toolkit facilitates the simultaneous examination of temporal progression and T-cell profiles using high-dimensional flow cytometric data. Employing novel algorithms based on canonical correspondence analysis and network analysis, our toolkit identifies developmental trajectories and analyses dynamic changes in developing cells. The efficacy of this approach is demonstrated by analysing thymic T cells from Nr4a3-Tocky mice, which monitor activities downstream of the T-cell receptor (TCR) signal. Further validation was achieved by deleting the proapoptotic gene Bcl2l11 in Nr4a3-Tocky mice. This revealed dynamic changes in thymic T cells during cellular development and negative selection following TCR signalling. Overall, this study establishes a new method for analysing the temporal dynamics of individual developing cells in response to in vivo signalling cues.

High Extracellular K+ Skews T-Cell Differentiation Towards Tumour Promoting Th2 and Treg Subsets.

Potassium ions (K+) released from dying necrotic tumour cells accumulate in the tumour microenvironment (TME) and increase the local K+ concentration to 50mM (high-[K+]e). Here, we demonstrate that high-[K+]e decreases expression of the T-cell receptor subunits CD3ε and CD3ζ and co-stimulatory receptor CD28 and thereby dysregulates intracellular signal transduction cascades. High-[K+]e also alters the metabolic profiles of T-cells, limiting the metabolism of glucose and glutamine, consistent with functional exhaustion. These changes skew T-cell differentiation, favouring Th2 and iTreg subsets that promote tumour growth while restricting antitumour Th1 and Th17 subsets. Similar phenotypes were noted in T-cells present within the necrosis-prone core versus the outer zones of hepatocellular carcinoma (HCC)/colorectal carcinoma (CRC) tumours as analysed by GeoMx digital spatial profiling and flow-cytometry. Our results thus expand the understanding of the contribution of high-[K+]e to the immunosuppressive milieu in the TME.

Antiviral potential of Vδ2 T-cells in children given TCR αβ/CD19 cell depleted HLA-haploidentical HSCT.

γδ T-cells represent key players in the immune-surveillance after TCR alpha/beta (αβ)/CD19-depleted HLA-Haploidentical Stem Cell Transplantation (haplo-HSCT). Although encouraging data are available on the impact of Vδ2-targeting-therapy in improving HSCT-clinical outcomes, their role in providing antimicrobial immunity is largely unexplored. This study aimed to investigate the antiviral protective profile of Vδ2 T-cells in pediatric patients given this type of allograft. The characterization of γδ T-cells was performed by flow cytometry in haplo-HSCT-pediatric patients (n=26) in the donor graft and after 30, 60 and 120 days post-HSCT. The antiviral activity of Vδ2 T-cells was assessed on CMV-infected-fibroblasts and the CMV-specific αβ T-cell immunity was analyzed by flow cytometry. Early after HSCT, frequency of Vδ2 T-cells was significantly higher in patients who did not experience viral reactivation (No-VR) than in patients with CMV reactivation (CMV-R). Interestingly, this difference was already present in the grafts. Clustering analysis identified a protective subset of Vδ2 T-cells in No-VR patients, which expresses CD16, NKG2D, and CD107a and produces high levels of IFN-γ. This subset directly correlated with IL-15 and inversely with the CMV-DNA level. Stimulated Vδ2 T-cells inhibit CMV replication, acquired CD86/HLA-DR molecules, induced HLA-DR on monocytes, and improved the αβ CMV-specific T-cell response. Altogether, these results identify an antiviral protective profile displayed by Vδ2 T-cells early after HSCT, and define their ability to inhibit CMV replication, to induce antigen-presenting cell maturation and to improve αβ virus-specific T-cell response, opening a new application of Vδ2-targeting immunotherapy after HSCT, adding the antiviral to the antitumor potential.

Modulation of TCR stimulation and pifithrin-α improve the genomic safety profile of CRISPR-engineered human Tcells.

CRISPR-engineered chimeric antigen receptor (CAR) Tcells are at the forefront of novel cancer treatments. However, several reports describe the occurrence of CRISPR-induced chromosomal aberrations. So far, measures to increase the genomic safety of Tcell products focused mainly on the components of the CRISPR-Cas9 system and less on Tcell-intrinsic features, such as their massive expansion after Tcell receptor (TCR) stimulation. Here, we describe driving forces of indel formation in primary human Tcells. Increased Tcell activation and proliferation speed correlate with larger deletions. Editing of non-activated Tcells reduces the risk of large deletions with the downside of reduced knockout efficiencies. Alternatively, the addition of the small-molecule pifithrin-α limits large deletions, chromosomal translocations, and aneuploidy in a p53-independent manner while maintaining the functionality of CRISPR-engineered Tcells, including CAR Tcells. Controlling Tcell activation and pifithrin-α treatment are easily implementable strategies to improve the genomic integrity of CRISPR-engineered Tcells.

STEM-01. SHARED ASTROCYTE-LIKE GLIOMA STEM CELLS DRIVE HETEROGENEITY AND IMMUNE DYNAMICS IN ADULT-TYPE DIFFUSE GLIOMAS

Abstract Adult-type diffuse gliomas present significant treatment challenges due to their complex cellular composition and evolving nature. Understanding this heterogeneity is critical for the development of effective, targeted therapies. We conducted single-cell and single-nucleus RNA sequencing on a unique cohort of 66 tumours (single surgery) and 54 paired samples (two surgeries). This comprehensive dataset of approximately 900,000 cells allows us to dissect conserved cellular landscapes and dynamic evolution across diverse glioma subtypes. Using a novel phylogeny-based approach, we identified an astrocyte-like glioma stem cell (GSC) as the root of diverse glioma lineages. This discovery transforms our understanding of glioma development, pinpointing the GSC as a potential therapeutic target. The GSC’s similarity to healthy adult neural stem cells provides clues as to the origin of glioma heterogeneity and the shared basis of intratumoural diversity. Our analysis uncovered a shared cellular architecture across astrocytomas, oligodendrogliomas, and glioblastomas (GBMs). This architecture encompasses seven recurring malignant cell states: neuro-, oligo-, neuro-oligo-lineage, cycling (G1/S, G2/M), hypoxia-associated, and a quiescent astrocyte-like GSC. Importantly, these cell state proportions vary significantly between glioma subtypes. Additionally, we demonstrate that GBMs display substantially higher T-cell and myeloid cell infiltration than IDH-mutant gliomas. Counterintuitively, this correlates with a poorer prognosis, implying profound T-cell dysfunction and intricate myeloid cell-tumour interactions. Longitudinal analysis further highlights the dynamic nature of glioma cell populations and the immune landscape. Subtype-specific T-cell and myeloid gene expression profiles were identified, including potential targets such as PARD6G (GBM) and CXCL13 (IDH-mutant-astrocytoma), laying the groundwork for tailored immunotherapies and prognostic biomarkers. This study presents a comprehensive model of glioma heterogeneity and evolution. The model reveals a shared astrocyte-like GSC that fuels cellular diversity, coupled with distinct, dynamic immune landscapes in different glioma subtypes. These findings hold extraordinary potential for developing transformative treatment strategies. Future research functionally validating the GSC and its impact on tumour dynamics will be essential for translating these insights into improved patient outcomes.

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.

Differential T-cell profiles determined by Hepatitis B surface antigen decrease among people with Human Immunodeficiency Virus /Hepatitis B Virus coinfection on treatment

BackgroundSeveral studies have reported that combination antiretroviral therapy (cART) enhances the hepatitis B surface antigen (HBsAg) clearance rate in Human Immunodeficiency Virus-1/Hepatitis B Virus (HIV/HBV) coinfected patients, yet the associated immunological characteristics remain unclear.MethodsGlobal and specific immune phenotypic profiles were examined in 48 patients with HIV/HBV coinfection before cART and at 1-year, and 3-year after cART using flow cytometry. In addition, 61 patients with HBV monoinfection were included for comparison.ResultsHBsAg response (sAg-R) was defined as > 0.5 log decrease within six months of cART initiation, and 16 patients achieved it. Patients with sAg-R (the sAg-R group) exhibited distinct immune phenotypes compared to those of HBsAg-retained patients (the sAg-NR group). Notably, patients with sAg-R had lower CD4+ T cell counts and a higher number of HBcAg-specific T cells. Further, the sAg-R group exhibited upregulation of HLA-DR, Ki67, and PD-1 in CD4+ T cells and heightened HLA-DR and T-bet in CD8+ T cells. However, the sAg-R group had fewer TEMRA cells but more TEM and Th17 cells than those in the sAg-NR group. Expression of various markers, including HLA-DR+CD4+, Ki67+CD4+, PD-1+CD4+, CD38+CD8+, HLA-DR+CD8+, TIM-3+CD8+, HBV-specific CD4+ T cell secreting IFN-γ and IL-2, and specific CD8+ T cell secreting IFN-γ and IL-2, correlated with HBsAg decrease.ConclusionThe decline in HBsAg levels during cART in HIV/HBV coinfection involves significant alterations in CD4+ and CD8+ T cells phenotypes, offering a novel perspective on a functional HBV cure.

A unique human cord blood CD8+CD45RA+CD27+CD161+ T-cell subset identified by flow cytometric data analysis using Seurat.

Advances in single-cell level analytical techniques, especially cytometric approaches, have led to profound innovation in biomedical research, particularly in the field of clinical immunology. This has resulted in an expansion of high-dimensional data, posing great challenges for comprehensive and unbiased analysis. Conventional manual analysis is thus becoming untenable to handle these challenges. Furthermore, most newly developed computational methods lack flexibility and interoperability, hampering their accessibility and usability. Here, we adapted Seurat, an R package originally developed for single-cell RNA sequencing (scRNA-seq) analysis, for high-dimensional flow cytometric data analysis. Based on a 20-marker antibody panel and analyses of T-cell profiles in both adult blood and cord blood (CB), we showcased the robust capacity of Seurat in flow cytometric data analysis, which was further validated by Spectre, another high-dimensional cytometric data analysis package, and conventional manual analysis. Importantly, we identified a unique CD8+ T-cell population defined as CD8+CD45RA+CD27+CD161+ T cell that was predominantly present in CB. We characterised its IFN-γ-producing and potential cytotoxic properties using flow cytometry experiments and scRNA-seq analysis from a published dataset. Collectively, we identified a unique human CB CD8+CD45RA+CD27+CD161+ T-cell subset and demonstrated that Seurat, a widely used package for scRNA-seq analysis, possesses great potential to be repurposed for cytometric data analysis. This facilitates an unbiased and thorough interpretation of complicated high-dimensional data using a single analytical pipeline and opens a novel avenue for data-driven investigation in clinical immunology.

An inflammatory liquid fingerprint predicting tumor recurrence after liver transplantation for hepatocellular carcinoma.

Tumor recurrence is a life-threatening complication after liver transplantation (LT) for hepatocellular carcinoma (HCC). Precise recurrence risk stratification before transplantation is essential for the management of recipients. Here, we aimed to establish an inflammation-related prediction model for posttransplant HCC recurrence based on pretransplant peripheral cytokine profiling. Two hundred and ninety-three patients who underwent LT in two independent medical centers were enrolled, and their pretransplant plasma samples were sent for cytokine profiling. We identified four independent risk factors, including alpha-fetoprotein, systemic immune-inflammation index, interleukin 6, and osteocalcin in the training cohort (n=190) by COX regression analysis. A prediction model named inflammatory fingerprint (IFP) was established based on the above factors. The IFP effectively predicted posttransplant recurrence (area under the receiver operating characteristic curve [AUROC]: 0.792, C-index: 0.736). The high IFP group recipients had significantly worse 3-year recurrence-free survival rates (37.9vs. 86.9%, p<0.001). Simultaneous T-cell profiling revealed that recipients with high IFP were characterized by impaired T cell function. The IFP also performed well in the validation cohort (n=103, AUROC: 0.807, C-index: 0.681). In conclusion, the IFP efficiently predicted posttransplant HCC recurrence and helped to refine pretransplant risk stratification. Impaired T cell function might be the intrinsic mechanism for the high recurrence risk of recipients in the high IFP group.

Intratumoral T-cell composition predicts epcoritamab-based treatment efficacy in B-cell non-Hodgkin lymphomas.

Leveraging endogenous tumor-resident T-cells for immunotherapy using bispecific antibodies (BsAb) targeting CD20 and CD3 has emerged as a promising therapeutic strategy for patients with B-cell non-Hodgkin lymphomas. However, features associated with treatment response or resistance are unknown. To this end, we analyzed data from patients treated with epcoritamab-containing regimens in the EPCORE NHL-2 trial (NCT04663347). We observed downregulation of CD20 expression on B-cells following treatment initiation both in progressing patients and in patients achieving durable complete responses (CR), suggesting that CD20 downregulation does not universally predict resistance to BsAb-based therapy. Single-cell immune profiling of tumor biopsies obtained following one cycle of therapy revealed substantial clonal expansion of cytotoxic CD4+ and CD8+ T-cells in patients achieving CR, and an expansion of follicular helper and regulatory CD4+ T-cells in patients whose disease progressed. These results identify distinct tumor-resident T-cell profiles associated with response or resistance to BsAb therapy.

Consideration of T-Cell Profile in the Examination of Statin Efficacy in Inflammatory Diseases, Neurodegeneration, and Neurocognitive Performance.

Statins are a cornerstone in the medical management of cardiovascular disease, yet their efficacy varies greatly between individuals. In this commentary, we outline the evidence for the role of CD4+CD28null T-cell expansion as a critical moderator of the effects of statins in preventing cardiovascular events via the reduction of pathological inflammation. Given this relationship, we argue that T-cell profiles should be considered as a patient characteristic in clinical and preclinical studies examining statin efficacy in other age- and inflammation-related pathologies. We discuss the implications this may have for studies of statin use in numerous disease processes-notably, dementia and neurocognitive dysfunction-and the potential for T-cell profiles to be used as a prognosticator for statin efficacy in rheumatoid arthritis, Alzheimer's disease, and multiple sclerosis.

Adaptive digital tissue deconvolution.

The inference of cellular compositions from bulk and spatial transcriptomics data increasingly complements data analyses. Multiple computational approaches were suggested and recently, machine learning techniques were developed to systematically improve estimates. Such approaches allow to infer additional, less abundant cell types. However, they rely on training data which do not capture the full biological diversity encountered in transcriptomics analyses; data can contain cellular contributions not seen in the training data and as such, analyses can be biased or blurred. Thus, computational approaches have to deal with unknown, hidden contributions. Moreover, most methods are based on cellular archetypes which serve as a reference; e.g. a generic T-cell profile is used to infer the proportion of T-cells. It is well known that cells adapt their molecular phenotype to the environment and that pre-specified cell archetypes can distort the inference of cellular compositions. We propose Adaptive Digital Tissue Deconvolution (ADTD) to estimate cellular proportions of pre-selected cell types together with possibly unknown and hidden background contributions. Moreover, ADTD adapts prototypic reference profiles to the molecular environment of the cells, which further resolves cell-type specific gene regulation from bulk transcriptomics data. We verify this in simulation studies and demonstrate that ADTD improves existing approaches in estimating cellular compositions. In an application to bulk transcriptomics data from breast cancer patients, we demonstrate that ADTD provides insights into cell-type specific molecular differences between breast cancer subtypes. A python implementation of ADTD and a tutorial are available at Gitlab and zenodo (doi:10.5281/zenodo.7548362).

Circulating memory T cells and TCF1+ T cells aid in diagnosis and monitor disease activity in vitiligo

Vitiligo is an immune memory skin disease. T-cell factor 1 (TCF1) is essential for maintaining the memory T-cell pool. There is an urgent need to investigate the characteristics of peripheral memory T-cell profile and TCF1+ T-cell frequencies in patients with vitiligo. In this study, 31 patients with active vitiligo (AV), 22 with stable vitiligo (SV), and 30 healthy controls (HCs) were included. We measured circulating memory and TCF1+ T-cell frequencies using flow cytometry. The Spearman's rank test was used to evaluate the correlation between cell frequencies and disease characteristics. Receiver operating characteristic curves (ROC) were constructed to investigate the discriminative power of the cell subpopulations. Circulating CD4+ and CD8+ terminally differentiated effector memory T-cell (TEMRA) frequencies were significantly higher in the AV group than in HCs (P < 0.05). TCF1+ T-cell subpopulations were widespread increased in patients with vitiligo (P < 0.05). After adjusting for potential confounders, CD8+ and CD4+ central memory (TCM) cells, and CD8+ TEMRA were correlated with disease activity (P < 0.05). The combined diagnostic value of the four (naïve, effector memory, TCM, and TEMRA) CD8+TCF1+ T-cell subsets was relatively high (area under the ROC curve (AUC) = 0.804, sensitivity = 71.70%, specificity = 83.34%), and the CD8+ T-cell subsets combination performed well in discriminating disease activity (AUC = 0.849, sensitivity = 70.97%, specificity = 90.91%). We demonstrated an altered circulating memory T-cell profile and increased TCF1+ T-cell percentage in patients with vitiligo. T-cell subpopulations had a strong value for vitiligo diagnosis and activity evaluation. This evidence presents a potential new pharmacological target for inhibiting autoimmunity that leads to vitiligo.

Correlation of immune fitness with response to teclistamab in relapsed/refractory multiple myeloma in the MajesTEC-1 study

AbstractTeclistamab, an off-the-shelf B-cell maturation antigen (BCMA) × CD3 bispecific antibody that mediates T-cell activation and subsequent lysis of BCMA-expressing myeloma cells, is approved for the treatment of patients with relapsed/refractory multiple myeloma (R/RMM). As a T-cell redirection therapy, clinical outcomes with teclistamab may be influenced by patient immune fitness and tumor antigen expression. We correlated tumor characteristics and baseline immune profiles with clinical response and disease burden in patients with R/RMM from the pivotal phase 1/2 MajesTEC-1 study, focusing on patients treated with 1.5 mg/kg of teclistamab (N = 165). Peripheral blood samples were collected at screening, and bone marrow samples were collected at screening and cycle 3. Better clinical outcomes to teclistamab correlated with higher baseline total T-cell counts in the periphery. In addition, responders (partial response or better) had a lower proportion of immunosuppressive regulatory T cells (Tregs), T cells expressing coinhibitory receptors (CD38, PD-1, and PD-1/TIM-3), and soluble BCMA and a T-cell profile suggestive of a more cytolytic potential, compared with nonresponders. Neither frequency of baseline bone marrow BCMA expression nor BCMA-receptor density was associated with clinical response to teclistamab. Improved progression-free survival was observed in patients with a lower frequency of T cells expressing exhaustion markers and immunosuppressive Tregs. Overall, response to teclistamab was associated with baseline immune fitness; nonresponders had immune profiles suggestive of immune suppression and T-cell dysfunction. These findings illustrate the importance of the contribution of the immune landscape to T-cell redirection therapy response. This trial was registered at www.ClinicalTrials.gov as #NCT03145181/NCT04557098.