Cytotoxic T Lymphocytes Research Articles

Exploring the Impact of Meditation Therapy on CD4 Levels in HIV/AIDS Patients at Karawang Hospital

Background: The HIV/AIDS epidemic remains a significant global health concern, with increasing prevalence in Indonesia's Karawang Regency. People living with HIV/AIDS face numerous challenges, including a decline in immune function and CD4 T-cell depletion. While antiretroviral therapy (ART) is the primary treatment, there is a growing interest in complementary therapies to support immune function and overall well-being. Objective: This study aimed to investigate the effect of meditation therapy on CD4 levels in HIV/AIDS patients at Karawang Regional General Hospital. Methods: A quasiexperimental study with a prepost design was conducted on 15 HIV/AIDS patients with CD4 levels ranging from 200–500 cells/mm3. The participants engaged in meditation sessions twice a week, twice daily, for one month. CD4 levels were measured before and after the intervention. Demographic data were collected, and statistical analyses were performed via paired t tests (p<0.05). Results: Most of the participants were male (80%), aged 31-37 years (46.7%), and had a vocational high school education (40%). Preintervention CD4 levels ranged from 226 to 459 cells/mm3 (mean: 334.87±57.583), whereas postintervention levels ranged from 220 to 467 cells/mm3 (mean: 340.93±62.721). A paired t test revealed no statistically significant effect of meditation therapy on CD4 levels (p=0.150). Conclusion: This study revealed no significant increase in CD4 levels following a one-month meditation intervention in HIV/AIDS patients. While this research does not support the use of short-term meditation therapy to increase CD4 levels in HIV/AIDS patients, it underscores the need for further investigation of complementary therapies for this population.

Profile of Clinical, Radiological and Laboratory Pattern in TB-HIV Coinfection in National Infection Centre of Indonesia

Background: The study aims to map TB (Tuberculosis) – HIV (Human Immunodeficiency Virus) patients based on clinical, radiological, and laboratory patterns. Objective: This study is expected to provide previous research investigating radiologic and laboratory examinations in TB-HIV patients. Method: We conducted a cross-sectional study based on medical records of TB-HIV patients at RSPI Sulianti Saroso from January 2004 - March 2017. Samples were 240 TB-HIV patients from a population of 1014 People Living with HIV/AIDS (PLWHA). Inclusion criteria were PLWHA, aged over 18 years, diagnosed with TB with completed medical record status. Result: Characteristics of the majority of patients were in the productive age group (99.2%) with an average age of 33 years and male sex (78%). The main symptom is cough (91.7%) and cough with phlegm (59.1%). Most patients (83.37%) have not received ART (Anti-Retroviral Therapy). Pulmonary physical examination showed that most patients had Ronchi (95.8%) while others got wheezing (5%). Laboratory tests revealed an initial CD4 cell count of 71.6 cells/ml and a negative Acid-Fast Bacillus (AFB) smear (59.2%). The patient's radiology was mainly with an infiltrate (82.5%); most infiltrate was presented in apex (52.4%). Conclusion: The majority of TB-HIV coinfected patients are young males, presenting with common TB symptoms, low CD4 counts, and negative AFB smears, complicating diagnosis. Radiological findings frequently show infiltrates, particularly in the apex. These findings emphasize the importance of early diagnosis and ART initiation to improve outcomes in TB-HIV coinfected patients

Construction of DNA Vaccine of Extracellular Region of Vascular Endothelial Growth Factor Receptor 2 and Its Antitumor Activity in Vivo

Introduction: it constructed recombinant DNA vaccine of extracellular region of vascular endothelial growth factor receptor 2 (VEGFR2) and analyzed its in vivo activity against H22 transplanted hepatoma. Methods: the gene fragment of VEGFR2 extracellular region 1-3 was amplified, and the pcDNA3.1(+)/exVEGFR2 recombinant plasmid was constructed. The expression of exVEGFR2 was detected by Western blot. Subsequently, liposome (LP) pcDNA3.1(+)/exVEGFR2 complex (LP-pcDNA3.1(+)/exVEGFR2) was prepared and immunized to C57BL/6 mice. The cytotoxic activity mediated by cytotoxic T cells (CTLs) was analyzed by 51Cr release assay. H22 tumor bearing C57BL/6 mouse model was prepared. Quadriceps femoris muscle was injected with normal saline (saline group, AG), LP-pcDNA3.1(+) 100 μL (1 μg/μL, LP-pcDNA3.1(+) group, BG), and LP-pcDNA3.1(+)/exVEGFR2 100 μL (1 μg/μL, LP-pcDNA3.1(+)/exVEGFR2 group, CG). Tumor growth and death were recorded, and microvessel density (MVD) was evaluated by CD31 immunohistochemical staining. Results: a 1252 bp of exVEGFR2 sequence was amplified, and a specific band expressing 44 kDa molecular weight was constructed by transfecting pcDNA3.1(+)/exVEGFR2 into COS-7 cells. After immunizing C57BL/6 mice for 6 weeks, CTLs experiment suggested that LP-pcDNA3.1(+)/exVEGFR2 could effectively mediate the toxic effect of VEGFR2 positive H22 cells. The in vivo antitumor activity experiment found that as against AG and BG, the tumor volume, weight, and MVD were markedly reduced, the tumor latency time was markedly prolonged, and the average survival time was also markedly prolonged in CG (P < 0.05). Conclusion: LP-pcDNA3.1(+)/exVEGFR2 can effectively activate C57BL/6 mice to produce specific anti-VEGFR2 immune response, and then produce anti-tumor cell immunotoxicity in vitro and in vivo. Inhibiting angiogenesis can effectively prolong the survival time of H22 tumor bearing mice.

Light-Driven Green-Fabricated Artificial Intelligence-Enabled Micro/Nanorobots for Multimodal Phototherapeutic Management of Bladder Cancer.

Combination therapy based on precise phototherapies combined withimmunemodulation provides successful antitumor effects. In this study, a combination therapy is designed based on phototactic, photosynthetic, and phototherapeutic Chlamydomonas Reinhardtii (CHL)-glycol chitosan (GCS)-polypyrrole (PPy) nanoparticle (NP)-enhanced immunity combined with the tumor microenvironment turnover of cytotoxic Tcells and M1/M2 macrophages, which is based on photothermal GCS-PPy NPsdecorated onto the phototactic and photosyntheticCHL. Phototherapy based on CHL-GCS-PPy NPs alleviates hypoxia and modulates the tumor immunemicroenvironment, which induces tumor cell death. In particular, the precise antitumor immune response and potent immune memory induced by combining self-navigated phototherapies significantly alleviate the progression of bladder cancer in C57BL/6 mice and effectively inhibit bladder tumor growth. Furthermore, they also potentially prevent tumor recurrence, which provides a promising therapeutic strategy for clinical tumor therapy.

Novel protein-based prognostic signature linked to immunotherapeutic efficiency in ovarian cancer

BackgroundPersonalized medicine remains an unmet need in ovarian cancer due to its heterogeneous nature and complex immune microenvironments, which has gained increasing attention in the era of immunotherapy. A key obstacle is the lack of reliable biomarkers to identify patients who would benefit significantly from the therapy. While conventional clinicopathological factors have exhibited limited efficacy as prognostic indicators in ovarian cancer, multi-omics profiling presents a promising avenue for comprehending the interplay between the tumor and immune components. Here we aimed to leverage the individual proteomic and transcriptomic profiles of ovarian cancer patients to develop an effective protein-based signature capable of prognostication and distinguishing responses to immunotherapy.MethodsThe workflow was demonstrated based on the Reverse Phase Protein Array (RPPA) and RNA-sequencing profiles of ovarian cancer patients from The Cancer Genome Atlas (TCGA). The algorithm began by clustering patients using immune-related gene sets, which allowed us to identify immune-related proteins of interest. Next, a multi-stage process involving LASSO and Cox regression was employed to distill a prognostic signature encompassing five immune-related proteins. Based on the signature, we subsequently calculated the risk score for each patient and evaluated its prognostic performance by comparing this model with conventional clinicopathological characteristics.ResultsWe developed and validated a protein-based prognostic signature in a cohort of 377 ovarian cancer patients. The risk signature outperformed conventional clinicopathological factors, such as age, grade, stage, microsatellite instability (MSI), and homologous recombination deficiency (HRD) status, in terms of prognoses. Patients in the high-risk group had significantly unfavorable overall survival (p < 0.001). Moreover, our signature effectively stratified patients into subgroups with distinct immune landscapes. The high-risk group exhibited higher levels of CD8 T-cell infiltration and a potentially greater proportion of immunotherapy responders. The co-activation of the TGF-β pathway and cancer-associated fibroblasts could impair the ability of cytotoxic T cells to eliminate cancer cells, leading to poor outcomes in the high-risk group.ConclusionsThe protein-based signature not only aids in evaluating the prognosis but also provides valuable insights into the tumor immune microenvironments in ovarian cancer. Together our findings highlight the importance of a thorough understanding of the immunosuppressive tumor microenvironment in ovarian cancer to guide the development of more effective immunotherapies.

Adverse reactions of immune checkpoint inhibitors combined with Proton pump inhibitors: a pharmacovigilance analysis of drug-drug interactions

BackgroundCombining immune checkpoint and proton pump inhibitors is widely used in cancer treatment. However, the drug-drug interactions of these substances are currently unknown. This study aimed to explore drug-drug interactions associated with concomitant immune checkpoint and proton pump inhibitors.MethodsData were obtained from the US Food and Drug Administration Adverse Event Reporting System from 2014 to 2023. Disproportionality analysis was used for data mining by calculating the reporting odds ratios (RORs) with 95% confidence intervals (95%Cls). The adjusted RORs (RORadj) were then analysed using logistic regression analysis, considering age, sex, and reporting year. Drug-drug interactions occur when a combination treatment enhances the frequency of an event. Further confirmation of the robustness of the findings was achieved using additive and multiplicative models, which are the two statistical methodologies for signal detection of DDIs using spontaneous reporting system.ResultsThe total number of reports on immune checkpoint combined with proton pump inhibitors was 4,276. Median patient age was 66 years (interquartile range [IQR]: 60–74 years). Significant interaction signals were observed for congenital, familial and genetic disorders (RORadj = 2.66, 95%CI, 1.38–5.14, additive models = 0.7322, multiplicative models = 3.5142), hepatobiliary disorders (RORcrude = 6.64, 95%CI, 5.82–7.58, RORadj = 7.10, 95%CI, 6.16–8.18, additive models = 2.0525, multiplicative models = 1.1622), metabolism and nutrition disorders (RORcrude = 3.27, 95%CI, 2.90–3.69, RORadj = 2.66, 95%CI, 2.30–3.08, additive models = 0.6194), and skin and subcutaneous tissue disorders (RORcrude = 1.41, 95%CI, 1.26–1.58, RORadj = 1.53, 95%CI, 1.34–1.75, additive models = 0.6927, multiplicative models = 5.3599). Subset data analysis showed that programmed death-1 combined with proton pump inhibitors was associated with congenital, familial, and genetic disorders; hepatobiliary disorders; and skin and subcutaneous tissue disorders. Programmed death ligand-1 combined with proton pump inhibitors was associated with adverse reactions of metabolism and nutrition disorders. Cytotoxic T-lymphocyte antigen-4 combined with proton pump inhibitors was associated with congenital, familial, and genetic disorders, and skin and subcutaneous tissue disorders.ConclusionsBased on real-world data, four Standardized MedDRA Query System Organ Class toxicities were identified as drug-drug interactions associated with combining immune checkpoint and proton pump inhibitors. Clinicians should be cautious when administering these drugs concomitantly. Preclinical trials and robust clinical studies are required to explore the mechanisms and relationships underlying interactions, thus improving understanding of drug-drug interactions associated with this combination therapy.

Lymphocyte Function in Tertiary Lymphoid Structures Predicts Hepatocellular Carcinoma Outcome

An increasing number of studies have revealed a correlation between tertiary lymphoid structures (TLSs) and the outcome of hepatocellular carcinoma (HCC). Nevertheless, the associations between the heterogeneity of cellular composition and the overall survival (OS) in HCC remain unexplored. Here, we evaluated the cancer tissues from 150 HCC individuals treated at the Tumor Hospital Affiliated with Nantong University using multiplex immunofluorescence to determine the presence and characteristics of TLS and to investigate the relationship between intra-TLS immunologic activity, TLS maturation, and intratumoral immune cell infiltration. Prognostic factors influencing the outcome were identified through both univariate and multivariate analyses. Additionally, the levels of cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death 1, programmed death-ligand 1, and lymphocyte activation gene-3 were determined, as well as their relationship with TLS features were determined. TLS was detected in 71 (47.3%) of the 150 HCC cases and was related to higher intratumoral infiltration levels of lymphocytes. Additionally, intra-TLS lymphocyte proliferation correlated with that of intratumoral lymphocytes, and the presence of TLS and a high proportion of mature TLS demonstrated a significant correlation with better prognosis (P = .013 and P = .03, respectively). Among TLS-positive tumors, a high proportion of B cells expressing activation-induced cytidine deaminase and a high proportion of CD8+ T cells expressing CD45RO were significantly related to improved OS (P = .01 and P < .001, respectively). Comparatively, a high proportion of CD21+CD20+ B cells demonstrated a significant correlation with poorer OS (P < .002). A markedly reduced number of CTLA-4+ cells in the stromal regions in TLS-negative tumors was observed compared with TLS-positive tumors (P = .01). These findings reveal a correlation between TLS presence and improved OS in HCC patients. However, TLS exhibited significant variation in maturation state, T- and B-cell proliferation, and expression of markers related to B- and T-cell function. Notably, these characteristics were also found to possess prognostic significance, indicating that certain TLS might hinder tumor immunity by inhibiting immune cells, whereas others may foster antigen-driven immune responses, likely influenced by the composition and functional status of intra-TLS lymphocytes.

Global well-posedness and dynamics of spatial diffusion HIV model with CTLs response and chemotaxis

In this paper, we study the global well-posedness and global dynamics of a reaction–diffusion HIV infection model with the chemotactic movement of CTLs (Cytotoxic T lymphocytes). We first show the global existence and uniform boundedness for solutions of the system with general functional incidences. Then, for the model with bilinear incidence rate, we discuss the existence conditions of the three equilibria (infection-free, chemokines-extinct, chemokines-acute equilibria) of the model and obtain the conclusion of the local asymptotic stability of these equilibria by analyzing the linearized system at these equilibria. Moreover, by constructing reasonable Lyapunov functionals, we investigate the global stability and attractivity of the equilibria. Applying the Lp−Lq estimate, Young’s inequality, Gagiardo-Nirenberg inequality and the parabolic regularity theorem, we also discuss the convergence rates of the equilibria. Finally, some numerical simulations are conducted to verify the theoretical results.

Broadly cross-reactive immune responses in chickens immunized with chimeric virus-like particles of nodavirus displaying the M2e originated from avian and human influenza A viruses

Avian influenza A viruses (IAVs) pose a persistent threat to poultry industry worldwide, despite the presence of vaccines. Additionally, reverse-zoonosis transmission potentially introduces human-originated IAVs into poultry and complicates the efforts to control the spread of influenza. Current avian influenza vaccines are primarily based upon the rapidly mutating hemagglutinin (HA) and neuraminidase (NA) glycoproteins, which limit their efficacy against diverse strains of IAVs. Hence, the highly conserved ectodomains of matrix 2 protein (M2e) of IAVs are widely studied as alternatives to the HA and NA. However, the differences in the M2e amino acid sequences between avian and human IAVs generate antibodies that do not cross-react reciprocally with IAVs from other origins. To broaden and enhance the immunogenicity of M2e, we fused two copies each of the M2e derived from avian and human IAVs at the C-terminal end of the Macrobrachium rosenbergii nodavirus (MrNV) capsid protein (NvC). Transmission electron microscopic and dynamic light scattering analyses revealed that the chimeric protein self-assembled into virus-like particles (VLPs). Immunization of chickens with the chimeric VLPs demonstrated a robust induction of broadly reactive immune responses against both the M2e of avian and human IAVs. Additionally, the chimeric VLPs elicited the production of cytotoxic T lymphocytes (CTL), macrophages, as well as a well-balanced Th1 and Th2 population, indicating their potential in activating cell-mediated immune responses in chickens. Furthermore, the chimeric VLPs triggered the production of both Th1- and Th2-cytokines, attesting their potential in mounting a robust and balanced immune response in avian species. This study demonstrated the potential of these chimeric VLPs in stimulating and broadening cross-reactive immune responses in chickens against both avian and human IAVs.

Autophagy Blockage Up-Regulates HLA-Class-I Molecule Expression in Lung Cancer and Enhances Anti-PD-L1 Immunotherapy Efficacy.

Immune checkpoint inhibitors have an established role in non-small cell lung cancer (NSCLC) therapy. The loss of HLA-class-I expression allows cancer cell evasion from immune surveillance, disease progression, and failure of immunotherapy. The restoration of HLA-class-I expression may prove to be a game-changer in current immunotherapy strategies. Autophagic activity has been recently postulated to repress HLA-class-I expression in cancer cells. NSCLC cell lines (A549 and H1299) underwent late-stage (chloroquine and bafilomycin) and early-stage autophagy blockage (ULK1 inhibitors and MAP1LC3A silencing). The HLA-class-I expression was assessed with flow cytometry, a Western blot, and RT-PCR. NSCLC tissues were examined for MAP1LC3A and HLA-class-I expression using double immunohistochemistry. CD8+ T-cell cytotoxicity was examined in cancer cells pre-incubated with chloroquine and anti-PD-L1 monoclonal antibodies (Moabs); Results: A striking increase in HLA-class-I expression following incubation with chloroquine, bafilomycin, and IFNγ was noted in A549 and H1299 cancer cells, respectively. This effect was further confirmed in CD133+ cancer stem cells. HLA-class-I, β2-microglobulin, and TAP1 mRNA levels remained stable. Prolonged exposure to chloroquine further enhanced HLA-class-I expression. Similar results were noted following exposure to a ULK1 and a PIKfyve inhibitor. Permanent silencing of the MAP1LC3A gene resulted in enhanced HLA-class-I expression. In immunohistochemistry experiments, double LC3A+/HLA-class-I expression was seldom. Pre-incubation of H1299 cancer cells with chloroquine and anti-PD-L1 MoAbs increased the mean % of apoptotic/necrotic cells from 2.5% to 18.4%; Conclusions: Autophagy blockers acting either at late or early stages of the autophagic process may restore HLA-class-I-mediated antigen presentation, eventually leading to enhanced immunotherapy efficacy.

PI3K/AKT/mTOR and PD‑1/CTLA‑4/CD28 pathways as key targets of cancer immunotherapy (Review).

T cells play an important role in cancer, and energy metabolism can determine both the proliferation and differentiation of T cells. The inhibition of immune checkpoint molecules programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) are a promising cancer treatment. In recent years, research on CD28 has increased. Although numerous reports involve CD28 and its downstream PI3K/AKT/mTOR signaling mechanisms in T cell metabolism, they have not yet been elucidated. A literature search strategy was used for the databases PubMed, Scopus, Web of Science and Cochrane Library to ensure broad coverage of medical and scientific literature, using a combination of keywords including, but not limited to, 'lung cancer' and 'immunotherapy'. Therefore, the present study reviewed the interaction and clinical application of the PD-1/CTLA-4/CD28 and PI3K/AKT/mTOR pathways in T cells, aiming to provide a theoretical basis for immunotherapy in clinical cancer patients.

Discovery of 2-Aryl-4-aminoquinazolin-Based LSD1 Inhibitors to Activate Immune Response in Gastric Cancer.

LSD1 (histone lysine-specific demethylase 1) has been gradually disclosed to act as an immunomodulator to enhance antitumor immune response. Despite the identification of numerous potent LSD1 inhibitors, there remains a lack of LSD1 inhibitors approved for marketing. Novel LSD1 inhibitors with different mechanisms are therefore needed. Herein, we reported a series of novel quinazoline-based LSD1 inhibitors. Among them, compound Z-1 exhibited the best LSD1 inhibitory activity (IC50 = 0.108 μM). Z-1 also acted as a selective and cellular active as an LSD1 inhibitor. Furthermore, Z-1 promoted response of gastric cancer cells to T-cell killing effect by decreasing PD-L1 expression and further attenuated the PD-1/PD-L1 interaction. In vivo, Z-1 exhibited significant suppression effect on the growth of gastric cancer cells without obvious toxicity. Therefore, Z-1 represents a potential novel immunomodulator that targets LSD1, providing a lead compound with new function mechanism for gastric cancer treatment.

Soluble cytotoxic T-lymphocyte antigen-4 (sCTLA-4) in children with immune cytopenia: relation to disease activity

Cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) is a costimulatory receptor exhibiting a potent inhibitory signal on antigen-activated immune responses. A soluble form, sCTLA-4, has been identified and was found to be increased in several autoimmune diseases. We aimed to evaluate serum levels of sCTLA-4 in different immune cytopenias, and to determine its possible relation to the disease activity. We measured serum levels of sCTLA-4 in 47 patients with immune cytopenias and compared them to 47 age- and sex-matched healthy controls. sCTLA-4 levels were significantly higher in patients with immune cytopenias compared to healthy controls (p < 0.001), however, levels were comparable between different groups of immune cytopenias (p = 0.084). Serum sCTLA-4 inversely correlated with age at diagnosis and hemoglobin level (p = 0.048, and p = 0.039 respectively), while it directly correlated with disease duration (p = 0.023) as well as markers of hemolysis including reticulocyte count, serum LDH and indirect bilirubin (p = 0.025; p = 0.019; p = 0.004 respectively). In the AIHA group, serum sCTLA-4 levels were significantly lower in patients in remission compared to patients with active disease (p = 0.026). Children with immune cytopenia exhibit significantly higher levels of circulating sCTLA-4 which correlated with disease activity, yet the prognostic significance and its use to tailor treatment regimen require additional studies.

Self-assembled PROTACs enable protein degradation to reprogram the tumor microenvironment for synergistically enhanced colorectal cancer immunotherapy

Both β-catenin and STAT3 drive colorectal cancer (CRC) growth, progression, and immune evasion, and their co-overexpression is strongly associated with a poor prognosis. However, current small molecule inhibitors have limited efficacy due to the reciprocal feedback activation between STAT3 and β-catenin. Inspired by the PROteolysis TArgeting Chimera (PROTAC), a promising pharmacological modality for the selective degradation of proteins, we developed a strategy of nanoengineered peptide PROTACs (NP-PROTACs) to degrade both β-catenin and STAT3 effectively. The NP-PROTACs were engineered by coupling the peptide PROTACs with DSPE-PEG via disulfide bonds and self-assembled into nanoparticles. Notably, the dual degradation of β-catenin and STAT3 mediated by NP-PROTACs led to a synergistic antitumor effect compared to single-target treatment. Moreover, NP-PROTACs treatment enhanced CD103+ dendritic cell infiltration and T-cell cytotoxicity, alleviating the immunosuppressive microenvironment induced by β-catenin/STAT3 in CRC. These results highlight the potential of NP-PROTACs in facilitating the simultaneous degradation of two pathogenic proteins, thereby providing a novel avenue for cancer therapy.

Codon optimized influenza H1 HA sequence but not CTLA-4 targeting of HA antigen to enhance the efficacy of DNA vaccines in an animal model

Infections caused by the influenza virus lead to both epidemic and pandemic outbreaks in humans and animals. Owing to their rapid production, safety, and stability, DNA vaccines represent a promising avenue for eliciting immunity and thwarting viral infections. While DNA vaccines have demonstrated substantial efficacy in murine models, their effectiveness in larger animals remains subdued. This limitation may be addressed by augmenting the immunogenicity of DNA-based vaccines. In the investigation here, protein expression was enhanced via codon optimization and then mouse cytotoxic T-lymphocyte antigen 4 (CTLA-4) was harnessed as a modulatory adjunct to bind directly to antigen-presenting cells. Further, the study evaluated the immunogenicity of two variants of the hemagglutinin (HA) antigen, i.e. the full-length and the C-terminal deletion versions. The study findings revealed that the codon-optimized HA gene (pcHA) led to increased protein synthesis, as evidenced by elevated mRNA levels. Codon optimization also significantly bolstered both cellular and humoral immune responses. In cytokine assays, all plasmid constructs, particularly pCTLA4-cHA, induced robust interferon (IFN)-γ production, while interleukin (IL)-4 levels remained uniformly non-significant. Mice immunized with pcHA displayed an augmented presence of IFNγ+ T-cells, underscoring the enhanced potency of the codon-optimized HA vaccine. Contrarily, CTLA-4-fused DNA vaccines did not significantly amplify the immune response.

Feline eosinophilic sclerosing fibroplasia associated with T-/natural killer-cell lymphoma.

Feline eosinophilic sclerosing fibroplasia (FESF) is a proliferative, inflammatory disease of the gastrointestinal tract and other sites, uncommonly diagnosed in the cat. This entity of uncertain etiology typically presents as a progressive mass lesion, mimicking a neoplastic process. In this case series, we present 17 cases of FESF associated with intralesional lymphoma. Histologic and immunohistochemical characterization of this unique lymphoma revealed that the neoplastic lymphocytes were immunopositive for CD56 and/ or CD3, suggesting a natural killer cell, natural killer T-cell, or T-cell origin. This case series represents the first description of this lymphoma subtype, for which the term eosinophilic sclerosing lymphoma is proposed.

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.

Establish a novel immune-related gene prognostic risk index (IRGPRI) associated with CD8+ cytotoxic T lymphocytes in non-small-cell lung cancer (NSCLC)

BackgroundThe aim of this study is to create an index called IRGPRI (immune-related gene prognostic risk index) that can be utilized for predicting the prognosis and assessing the efficacy of immune checkpoint inhibitors (ICIs) therapy in patients with non-small-cell lung cancer (NSCLC). MethodsDistinguishing gene expression patterns (DEGs) were detected in CD8+ cytotoxic T lymphocytes (CTLs) compared to other cellular types such as CD4 T cells, B cells, plasma cells, and CD8 Tex using the advanced technology of Single-cell RNA Sequencing (scRNA-seq). The construction of IRGPRI was accomplished by employing LASSO Cox regression analysis. We conducted a comparative analysis on clinical characteristics and molecular features, such as pathway enrichment and gene mutation, among the distinct subgroups of IRGPRI. Furthermore, we explored the correlation between immunological characteristics and IRGPRI subgroups to comprehensively assess the effectiveness of ICIs in NSCLC patients. ResultsA total of 109 genes were identified by intersecting immune-related genes with DEGs obtained from single-cell RNA sequencing data (GSE131907), specifically comparing CTLs to other cell types. From these, we selected 7 prognosis-related genes, namely TRBC1, HLA-DMA, CTSH, RAC1, CTSL, ANXA2, and CEBPB. These genes were used to construct the IRGPRI. The prognosis of patients diagnosed with NSCLC was found to be significantly better in the low-risk group compared to the high-risk group, as demonstrated by Kaplan-Meier (K-M) survival analysis. This observation was further confirmed through the utilization of data from the GEO cohort. The low-risk group demonstrated an increase in pathways linked with immune response, whereas the high-risk group exhibited a higher prevalence of pathways related to cancer. Furthermore, it was noted in the TCGA cohort that there existed a significant rise in the mutation frequency of every gene within the high-risk group as opposed to the low-risk group. Missense variation emerged as the most prevalent form of mutation. According to the analysis of immune cell infiltration and function, the comprehensive findings suggest that the group with a low risk is characterized by an increased presence of plasma cells, CTLs, T cells follicular helper, Tregs, and Dendritic cell resting. Additionally, they exhibit a higher score in terms of immune function for B cells, CD8+ T cells, checkpoint activity, T cell inhibition and stimulation. Moreover, this low-risk group demonstrates greater efficacy when treated with ICIs therapy compared to the high-risk group. ConclusionsOur research effectively developed and verified a unique IRGPRI, showcasing its association with immune-related characteristics. As a result, the potential of IRGPRI as a valuable biomarker for predicting prognosis and evaluating the effectiveness of ICIs treatment in cancer is evident.

Sirolimus reduces T cell cycling, immune checkpoint marker expression, and HIV-1 DNA in people with HIV

Key HIV cure strategies involve reversing immune dysfunction and limiting the proliferation of infected Tcells. We evaluate the safety of sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, in people with HIV (PWH) and study the impact of sirolimus on HIV-1 reservoir size and HIV-1-specific immunity in a single-arm study of 20weeks of treatment in PWH on antiretroviral therapy (ART). Sirolimus treatment does not impact HIV-1-specific CD8 Tcell responses but leads to a significant decrease in CD4+ Tcell-associated HIV-1 DNA levels at 20weeks of therapy in the primary efficacy population (n= 16; 31% decline, p=0.008). This decline persists for at least 12weeks following cessation of the study drug. Sirolimus treatment also leads to a significant reduction in CD4+ Tcell cycling and PD-1 expression on CD8+ lymphocytes. These data suggest that homeostatic proliferation of infected cells, an important mechanism for HIV persistence, is an intriguing therapeutic target.

Decreased CD3+CD56+ Natural Killer T Lymphocytes and Increased Human Leukocyte Antigen-DR+ Cells in the Inflamed Area of Pouchitis in Ulcerative Colitis Patients.

Pouchitis is an inflammatory condition that affects the ileal pouch during ileal pouch-anal anastomosis surgery. Despite its clinical significance, precise immunological mechanisms underlying pouchitis remain unclear. This study aimed to investigate the lymphocyte profile in the ileal pouch of patients with pouchitis compared to those with familial adenomatous polyposis (FAP) and ulcerative colitis without pouchitis using flow cytometry and immunohistochemical techniques. We prospectively analyzed endoscopic biopsy specimens from the ileal pouches of 15 patients and categorized them into three groups: FAP, ulcerative colitis with an inflammation-free pouch (UC-I), and ulcerative colitis with ulcers and/or erosions in the pouch (UC-UE). Flow cytometry was used to assess various T-lymphocyte markers, including cluster of differentiation (CD) 4, CD8, CD56, and human leukocyte antigen (HLA)-DR. Immunohistochemistry was performed to visualize the spatial distribution of CD3+, CD56+, and HLA-DR+ cells in the pouch mucosa. We observed significantly reduced CD56+/CD3+ and CD8+/CD3+ ratios in the UC-UE group compared to those in the FAP group, indicating a disruption in natural killer T-cell populations. Immunohistochemical analysis revealed that the spatial distribution of lymphocytes differed among the non-inflamed mucosa, dense lymphocyte infiltration, and lymphoid follicles, with these components frequently intermingling. CD56 + cells were less abundant in areas with dense lymphocyte infiltration, whereas HLA-DR+ cells were more abundant. Our study revealed a decrease in CD56+ natural killer T cells and an increase in HLA-DR+-activated T cells in areas with dense lymphocyte infiltration, suggesting an association between these cells and pouchitis in ulcerative colitis. The distinct patterns observed in non-inflamed mucosa, areas with dense lymphocyte infiltration, and lymphoid follicles underscore the need for further analyses of these three segments to elucidate the immunological mechanisms underlying pouchitis.