Immune Effector Research Articles

Vδ2 T-cell engagers bivalent for Vδ2-TCR binding provide anti-tumor immunity and support robust Vγ9Vδ2 T-cell expansion.

Vγ9Vδ2 T-cells are antitumor immune effector cells that can detect metabolic dysregulation in cancer cells through phosphoantigen-induced conformational changes in the butyrophilin (BTN) 2A1/3A1 complex. In order to clinically exploit the anticancer properties of Vγ9Vδ2 T-cells, various approaches have been studied including phosphoantigen stimulation, agonistic BTN3A-specific antibodies, adoptive transfer of expanded Vγ9Vδ2 T-cells, and more recently bispecific antibodies. While Vγ9Vδ2 T-cells constitute a sizeable population, typically making up ~1-10% of the total T cell population, lower numbers have been observed with increasing age and in the context of disease. We evaluated whether bivalent single domain antibodies (VHHs) that link Vδ2-TCR specific VHHs with different affinities could support Vγ9Vδ2 T-cell expansion and could be incorporated in a bispecific engager format when additionally linked to a tumor antigen specific VHH. Bivalent VHHs that link a high and low affinity Vδ2-TCR specific VHH can support Vγ9Vδ2 T-cell expansion. The majority of Vγ9Vδ2 T-cells that expanded following exposure to these bivalent VHHs had an effector or central memory phenotype and expressed relatively low levels of PD-1. Bispecific engagers that incorporated the bivalent Vδ2-TCR specific VHH as well as a tumor antigen specific VHH triggered antitumor effector functions and supported expansion of Vγ9Vδ2 T-cells in vitro and in an in vivo model in NOG-hIL-15 mice. By enhancing the number of Vγ9Vδ2 T-cells available to exert antitumor effector functions, these novel Vδ2-bivalent bispecific T cell engagers may promote the overall efficacy of bispecific Vγ9Vδ2 T-cell engagement, particularly in patients with relatively low levels of Vγ9Vδ2 T-cells.

An in-silico study of conventional and FLASH radiotherapy iso-effectiveness: potential impact of radiolytic oxygen depletion on tumor growth curves and tumor control probability

Objective. This work aims to investigate the iso-effectiveness of conventional and FLASH radiotherapy on tumors through in-silico mathematical models. We focused on the role of radiolytic oxygen depletion (ROD), which has been argued as a possible factor to explain the FLASH effect.Approach. We used a spatiotemporal reaction-diffusion model, including ROD, to simulate tumor oxygenation and response. From those oxygen distributions we obtained surviving fractions (SFs) using the linear-quadratic (LQ) model with the oxygen enhancement ratios (OERs). We then employed the calculated SFs to describe the evolution of preclinical tumor volumes through a mathematical model of tumor response, and we also extrapolated those results to calculate tumor control probabilities (TCPs) using the Poisson-LQ approach.Main results. Our study suggests that the ROD effect may cause differences in SF between FLASH and conventional radiotherapy, especially in lowα/βandpoorly oxygenatedcells. However, a statistical analysis showed that these changes in SF generally do not result in significant differences in the evolution of preclinical tumor growth curves when the sample size is small, because such differences in SF may not be noticeable in the heterogeneity of the population of animals. Nonetheless, when extrapolating this effect to TCP curves, we observed important differences between both techniques (TCP is lower in FLASH radiotherapy). When analyzing the response of tumors with heterogeneous oxygenations, differences in TCP are more important forwell oxygenatedtumors. This apparent contradiction with the results obtained for homogeneously oxygenated cells is explained by the complex interplay between the heterogeneity of tumor oxygenation, the OER effect, and the ROD effect.Significance. This study supports the experimentally observed iso-effectiveness of FLASH and conventional radiotherapy when analyzing the volume evolution of preclinical tumors (that are far from control). However, this study also hints that tumor growth curves may be less sensitive to small variations in SF than tumor control probability: ROD may lead to increased SF in FLASH radiotherapy, which while not large enough to cause significant differences in tumor growth curves, could lead to important differences in clinical TCPs. Nonetheless, it cannot be discarded that other effects not modeled in this work, like radiation-induced immune effects, can contribute to tumor control and maintain the iso-effectiveness of FLASH radiotherapy. The study of tumor growth curves may not be the ideal experiment to test the iso-effectiveness of FLASH, and experiments reporting TCP orD50may be preferred.

Immune Marker and C-Reactive Protein Dynamics and Their Prognostic Implications in Modulated Electro-Hyperthermia Treatment in Advanced Pancreatic Cancer: A Retrospective Analysis

Background: Previous research has suggested that modulated electro-hyperthermia (mEHT) can be used to induce anti-tumor immune effects and to extend patient survival. The use of mEHT in advanced pancreatic cancer is beneficial; however, its immune-mediating effects were never investigated. Methods: A retrospective observational study was conducted. Leukocyte counts, C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), and granulocyte-to-lymphocyte ratio (GLR) were measured at baseline, midpoint, and after mEHT treatment. Results: A total of 73 mEHT treated pancreatic cancer patients were included. The time elapsed between tumor diagnosis and the first mEHT treatment was 4.40 ± 5.70 months. While no change could be observed between the baseline and the first follow-up visits, the total white blood cell (WBC), neutrophil, and granulocyte count, CRP, NLR, and GLR were significantly higher at the second follow-up compared to both previous visits. Higher levels of the latter parameters following the last mEHT treatment were signaling significantly poor prognostic signs, and so were their longitudinal changes. Conclusions: After the initiation of mEHT, immune markers stabilize with the treatment, but this positive effect is eroded over time by progressive disease. Monitoring the changes in these markers and the occurrence of their increase is a prognostic marker of shorter survival.

Extracorporeal cytokine adsorption as therapeutic option for immune effector cell-associated neurotoxicity syndrome.

With the rising number of patients receiving chimeric antigen receptor T-cells, the treatment of this therapy's complications is of growing concern to intensivists and neurologists. We used extracorporeal cytokine adsorption as an add-on therapy in a patient suffering from immune effector cell-associated neurotoxicity syndrome. Interleukin-6 level, which as a readily available parameter is generally used to evaluate course of disease, was rapidly reduced using this method. The patient made a full recovery and is still in hematological remission.

Outcomes After Brexucabtagene Autoleucel Administered as a Standard Therapy for Adults With Relapsed/Refractory B-Cell ALL.

On the basis of the results of the ZUMA-3 trial, brexucabtagene autoleucel (brexu-cel), a CD19-directed chimeric antigen receptor T-cell therapy, gained US Food and Drug Administration approval in October 2021 for adults with relapsed/refractory (R/R) B-cell ALL (B-ALL). We report outcomes of patients treated with brexu-cel as a standard therapy. We developed a collaboration across 31 US centers to study adults with B-ALL who received brexu-cel outside the context of a clinical trial. Data were collected retrospectively from October 2021 to October 2023. Toxicities were graded per American Society for Transplantation and Cellular Therapy guidelines for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). At the time of data lock, 204 patients had undergone apheresis and 189 were infused. Median follow-up time was 11.4 months. Forty-two percent of patients received brexu-cel in morphologic remission and would have been ineligible for participation in ZUMA-3. After brexu-cel, 151 achieved complete remission (CR), of which 79% were measurable residual disease (MRD) negative remissions. Median progression-free survival (PFS) was 9.5 months and median overall survival was not reached. Grade 3-4 CRS or ICANS occurred in 11% and 31%, respectively. In multivariable analysis, patients receiving consolidative hematopoietic cell transplantation (HCT; hazard ratio, 0.34 [95% CI, 0.14 to 0.85]) after brexu-cel had superior PFS compared with those who did not receive any consolidation or maintenance therapy. Similar to ZUMA-3, high rates of MRD-negative CR were observed after brexu-cel treatment for R/R B-ALL. The use of HCT as consolidation after brexu-cel resulted in improved PFS.

What COVID-19 Vaccination Strategy Should Be Implemented and Which Vaccines Should Be Used in the Post-Pandemic Era?

COVID-19 vaccines have reduced the negative health and economic impact of the COVID-19 pandemic by preventing severe disease, hospitalizations and deaths. In the new socio-economic normality, the COVID-19 vaccination strategy can be universal or high-risk and seasonal or not seasonal, and different vaccines can be used. The universal vaccination strategy can achieve greater health and herd immunity effects and is associated with greater costs than the high-risk vaccination strategy. In each country, the optimal COVID-19 vaccination strategy must be decided by considering the advantages and disadvantages and assessing the costs, health effects and cost-effectiveness of the universal and high-risk vaccination strategies. The universal vaccination strategy should be implemented when the objective of the vaccination program is to achieve the greatest health benefits from COVID-19 vaccination and when its incremental cost-effectiveness ratio is lower than EUR 30,000-50,000 per QALY or LYG. The use of adapted vaccines targeting currently circulating variants of SARS-CoV-2 is necessary to avoid the immune escape of emerging variants.

Immune effector cell-associated enterocolitis following chimeric antigen receptor T-cell therapy in multiple myeloma

We report 14 cases of immune effector cell (IEC)-associated enterocolitis following chimeric antigen receptor T-cell (CAR-T) therapy in multiple myeloma, with a 1.2% incidence overall (0.2% for idecabtagene vicleucel and 2.2% for ciltacabtagene autoleucel). Patients developed acute-onset symptoms (typically non-bloody Grade 3+ diarrhea) with negative infectious workup beginning a median of 92.5 days (range: 22–210 days) after CAR-T therapy and a median of 85 days after cytokine release syndrome resolution. Gut biopsies uniformly demonstrated inflammation, including intra-epithelial lymphocytosis and villous blunting. In one case where CAR-specific immunofluorescence stains were available, CAR T-cell presence was confirmed within the lamina propria. Systemic corticosteroids were initiated in 10 patients (71%) a median of 25.5 days following symptom onset, with symptom improvement in 40%. Subsequent infliximab or vedolizumab led to improvement in 50% and 33% of corticosteroid-refractory patients, respectively. Five patients (36%) have died from bowel perforation or treatment-emergent sepsis. In conclusion, IEC-associated enterocolitis is a distinct but rare complication of CAR-T therapy typically beginning 1–3 months after infusion. Thorough diagnostic workup is essential, including evaluation for potential T-cell malignancies. The early use of infliximab or vedolizumab may potentially hasten symptom resolution and lower reliance on high-dose corticosteroids during the post-CAR-T period.

Understanding the probiotic potential of Lactobacillus plantarum: Antioxidant capacity, non-specific immunity and intestinal microbiota improvement effects on Manila clam Ruditapes philippinarum

Lactic acid bacteria (LAB) have beneficial effects on aquatic animals, improving their immune system and intestinal microbiota. Nevertheless, the probiotic effects of LAB on the Manila clam Ruditapes philippinarum remain poorly understood. Herein, the effects of administering Lactobacillus plantarum at final doses of 1 × 105 CFU/L (T5 group), 1 × 107 CFU/L (T7 group), and 1 × 109 CFU/L (T9 group) in the rearing water for eight weeks were evaluated for the antioxidant capacity, non-specific immunity, resistance to Vibrio parahaemolyticus infection, and intestinal microbiota of R. philippinarum. The rearing water without the addition of L. plantarum served as a control. The results showed that the T7 and T9 groups demonstrated a significant elevation in the disease resistance of clams against V. parahaemolyticus, in the activities of alkaline phosphatase and lysozyme in the hepatopancreas, and in the expression of antioxidant- and immune-related genes, including SOD, GPx, and GST. Meanwhile, the T7 group showed a significant enhancement in superoxide dismutase and catalase activities and CAT expression, while the T9 group experienced a remarkable elevation in reduced glutathione content. Only catalase activity was markedly elevated in the T5 group. The expression of SOD, CAT, GPx, and GST was significantly elevated in three treatment groups following the V. parahaemolyticus challenge. The T7 group exhibited a significant increase in intestinal microbiota richness. Significant increases were noted in Firmicutes abundance across all three treatment groups and in Actinobacteriota in the T5 and T7 groups. Additionally, the opportunistic pathogen Escherichia-Shigella abundance significantly decreased in three treatment groups. Furthermore, administration of 1 × 107 CFU/L L. plantarum enhanced the stability of the intestinal microecosystem, whereas a dose of 1 × 109 CFU/L might have a negative effect. The application of three doses of L. plantarum significantly enhanced intestinal microbiota functions related to the immune response and oxidative stress regulation, while a higher dose (1 × 109 CFU/L) might inhibit several functions. In conclusion, the application of L. plantarum in the rearing water exerted beneficial effects on the antioxidant capacity, non-specific immunity, resistance to V. parahaemolyticus, and the intestinal microbiota stability and functions of R. philippinarum. The beneficial effects of L. plantarum on R. philippinarum were dose-dependent, and the final dose of 1 × 107 CFU/L exhibited the optimal effects.

Anti-cancer immune effect of human colorectal cancer neoantigen peptide based on MHC class I molecular affinity screening.

Tumor antigen peptide vaccines have shown remarkable efficacy, safety, and reliability in recent studies. However, the screening process for immunopotent antigenic peptides is cumbersome, limiting their widespread application. Identifying neoantigen peptides that can effectively trigger an immune response is crucial for personalized cancer treatment. Whole exome sequencing was performed on patient-derived colon cancer cells to predict 9-amino-acid (9aa) neoantigen peptides. In vitro simulation of endogenous antigen presentation by antigen-presenting cells (dendritic cells) to CD8+ T cells was conducted, aiming to activate the CD8+ immune response to the predicted antigens. The immunological effects of each neoantigen were assessed using flow cytometry and ELISpot assays, while the relationship between neoantigen immunogenicity and MHC molecular affinity was examined. 1. Next-generation sequencing (NGS) predicted 9-amino acid (9aa) neoantigen peptides for subsequent immunological analysis.2. Higher mDC Levels in Experimental Group: CD11c+CD83+ mature dendritic cells (mDCs) were 96.6% in the experimental group, compared to 0.051% in the control group. CD80 fluorescence intensity was also significantly higher in the experimental group, confirming a greater mDC presence.3. Neoantigen Peptides Promote CD4+, CD8+ T, and NK Cell Proliferation: After 14 days, flow cytometry showed higher percentages of CD4+ T (37.41% vs 7.8%), CD8+ T (16.67% vs 14.63%), and NK cells (33.09% vs 7.81%) in the experimental group, indicating that the neoantigen peptides induced proliferation of CD4+, CD8+ T cells, and NK cells. 4. The results, analyzed using two-way ANOVA, showed that the standardized T-value for HLA molecular affinity variation in the 1-4 range (Group B) was significantly higher than for ≤1 (Group A, p < 0.0001) and >4 (Group C, p < 0.05). Regarding HLA-allele genotypes, HLA-Type 1 had a significantly higher standardized T-value than HLA-Type 2 (p < 0.05) and HLA-Type 3 (p < 0.0001). HLA-Type 1 was identified as the allele associated with the highest T-value. 1. The most immunogenic neoantigens typically exhibit an MHC molecular affinity variation between 1 and 4, indicating that stronger immunogenicity correlates with higher MHC molecular affinity variation. 2. Each patient's HLA molecules were classified into Types 1, 2, and 3, with Type 1 showing the highest binding capacity for neoantigens. Our findings indicate that the most immunogenic neoantigens were associated with HLA Type 1. 3. Neoantigen peptides were shown to activate the proliferation of both CD8+ T-cells and induce proliferation of CD4+ T-cells and NK cells. 4. Variation in MHC molecular affinity and HLA neoantigen genotype are anticipated to serve as valuable variables for screening highly immunogenic neoantigens, facilitating more efficient preparation of effective polypeptide tumor vaccines.

Robots and the corporate immunity–Evidence from the impact of the epidemic in China

ABSTRACT This paper investigates the influence of industrial robots on corporate immunity during the COVID-19 pandemic, utilising data from Chinese manufacturing listed companies between 2017Q1 and 2020Q1. The primary findings indicate that industrial robots can foster immunity to alleviate the adverse effects of the COVID-19 crisis, and this mitigation effect is substantial. The empirical results remain robust after conducting numerous tests and instrumental variable regression. The development of immunity by industrial robots occurs through two mechanisms: labour substitution and enhanced operational efficiency. The immunity effect of industrial robots is more pronounced in state-owned, high-tech firms, and companies severely impacted by the COVID-19 pandemic.

In Vivo Dynamics of HIV-1 Infection With Impaired Antibody Immunity and Three General Infection Mechanisms

In this paper we investigate two generalized human immunodeficiency virus type-1 (HIV-1) dynamics models with impaired antibody immunity. The models include both latently and actively infected cells. Three infection mechanisms are incorporated into the models, viral infection mechanism (VIM), latent cellular infection mechanism (CIM) and active CIM. The three infection rates are provided by generic nonlinear functions. The second model includes three types of distributed time delays. We find that our models are biologically feasible. The global stability analysis of equilibria are performed and found the basic reproduction ratio (R0) as a threshold parameter. Using Lyapunov method we show that, the virus-free equilibrium is globally asymptotically stable when R0≤1 and the virus-persistence equilibrium is globally asymptotically stable when R0&gt;1. Sensitivity analysis on R0 is studied. To support our theoretical results we provide some numerical simulations. We have demonstrated that R0 is influenced by all three of the infection types, and that if one of them were ignored, R0 would be underestimated. This might lead to inadequate medication effectiveness that aims to remove HIV-1 from the body. The effects of time delay and impaired antibody immunity on HIV-1 progression are examined. According to our research, lowered immunity is a significant factor in the infection's growth. Furthermore, time delays might drastically reduce R0, which would prevent HIV-1 from replicating. The information provided by our research in this work can improve our comprehension of HIV-1 dynamics within-host and provide guidance for the creation of novel pharmacological treatments.

Synthetic peptides as valuable and versatile tools for research: our 20 year journey in Chile

According to the International Union of Pure and Applied Chemistry (IUPAC), peptides are small proteins with a size between 2 and 50 amino acids residues. They are ubiquitous across the evolutionary scale, fulfilling a wide variety of functions, from immune system effectors in simple organisms to signaling or neuromodulating agents in high vertebrates. Following nature’s example, peptides have emerged as alternatives in various fields. One particularly relevant area is in drug discovery, offering alternatives to face the emergence of antibiotic-resistant microorganisms. Peptides are also prevalent in other sectors, such as the food industry, where they serve as food additives to enhance nutritional characteristics or aid in food preservation. Moreover, peptides are increasingly being utilized in cosmetics. Additionally, peptides serve as valuable tools in both basic and applied research, facilitating the exploration of specific activity mechanisms and the verification of particular activities, among various other applications. Despite certain limitations and disadvantages compared to other bioactive molecules, peptides remain a focal point of interest in research, as well as in applied and developmental fields, due to their versatility. In this report, we provide an overview of the extensive application landscape of synthetic peptides, presenting examples developed in-house across different areas which include a summary of the methodologies and results obtained.

Dysregulation of epigenetic modifications in inborn errors of immunity.

Inborn errors of immunity (IEIs) are a group of typically monogenic disorders characterized by dysfunction in the immune system. Individuals with these disorders experience increased susceptibility to infections, autoimmunity and malignancies due to abnormal immune responses. Epigenetic modifications, including DNA methylation, histone modifications and chromatin remodeling, have been well explored in the regulation of immune cell development and effector function. Aberrant epigenetic modifications can disrupt gene expression profiles crucial for immune responses, resulting in impaired immune cell differentiation and function. Dysregulation of these processes caused by mutations in genes involving in epigenetic modifications has been associated with various IEIs. In this review article, we focus on IEIs that are caused by mutations in 13 genes involved in the regulation of DNA methylation, histone modification and chromatin remodeling.

Incidence of immune effector cell-associated neurotoxicity among patients treated with CAR T-cell therapy for hematologic malignancies: systematic review and meta-analysis.

We aim to assess the pooled incidence of immune effector cell-associated neurotoxicity syndrome (ICANS) in clinical trials and real-world studies of chimeric antigen receptor (CAR) T-cell therapy for hematologic malignancy and compare the incidences among different agents. The PubMed, Embase, and Web of Science databases were searched for clinical trials and real-world studies. An inverse-variance weighting model was used to calculate pooled incidences and subgroup analyses. Multivariable analysis was conducted using binomial-normal modeling. Seventy-five trials comprising 3,184 patients were included. The overall pooled incidence was 26.9% (95% CI, 21.7-32.7%) for all-grade and 10.5% (95% CI, 8.1-13.6%) for high-grade ICANS. In subgroup analysis, cohorts with anti-CD19 drugs had significantly higher ICANS incidences than cohorts with other agents. The multivariable analysis demonstrated higher odds of ICANS in anti-CD19 drug studies for high-grade (OR, 4.6) compared to anti-BCMA drug studies. In 12 real-world studies, studies used axicabtagene ciloleucel with CD28 (54.0% all-grade, 26.4% high-grade) exhibited significantly higher rates of all-grade and high-grade ICANS than studies using tisagenlecleucel with 4-1BB (17.2% all-grade, 6.1% high-grade). The overall incidences of ICANS with CAR T-cell therapy were 26.9% for all-grade and 10.5% for high-grade. Compared with other agents, patients with anti-CD19 drugs had a significantly increased risk of developing high-grade ICANS. Therefore, careful monitoring of ICANS should be considered for patients undergoing CAR T-cell therapy.

Impact of Sex, Age and Body Habitus on RBD-specific Antibody Response After Two Doses of Sinopharm BBIBP-CorV Vaccine

Background: Mongolia started its nationwide vaccination campaign against COVID-19 on 23 February 2021 after receiving the first batch of the inactivated BBIBP-CorV. Age and body habitus of vaccinees may be associated with the immune effecter functions. Several systematic reviews and meta-analyses suggested lower immunogenicity of vaccines against SARS-CoV-2 infection in the older adult population and obese individuals. We aimed to establish a possible relationship between post-vaccine seroconversion rate and some biometric characteristics in the Mongolian cohort of vaccinees after two shots of the Sinopharm BBIBP-CorV vaccine. Materials and Methods: We collected serum samples from 846 eligible vaccinees before the first dose of the BBIBP-CorV vaccine and 21-28 days after the second dose of the same vaccine. Anti-SARS-CoV-2 Receptor Binding Domain (RBD) Immunoglobulin class G (IgG) and M (IgM) titer were measured in all samples. Results: 686 (81.1%) of 846 vaccinees received the Sinopharm BBIBP-CorV vaccine demonstrated seroconversion. Vaccinees with seroconversion had a younger mean age and lower mean body-mass index (BMI) than non-responders. Seroconversion rate according to age of vaccinees tends to decrease and obese vaccinees demonstrated a greater portion among non-responders. The Optimal Cut-Point (OCP) of age for seroconversion was found to differ significantly in male and female vaccinees. BMI has shown prediction ability for seroconversion only in male vaccinees but not in females. Using Receiver Operating Characteristics (ROC) analysis, we found 39 years for males and 41 years for females as a crucial milestone increasing the probability of seronegativity 2.5 times on average. A BMI higher than 29.1kg/m2 in male vaccinees was considered an acceptable predictor for seroconversion increasing the probability of seronegativity 2.4 times on average. Conclusion: The above findings allow us to summarize the sex-adjusted approach to biometric characteristics has an improved predictiveness for post-vaccine antibody response.

Efficient Treatment of Psoriasis Using Conditioned Media from Mesenchymal Stem Cell Spheroids Cultured to Produce Transforming Growth Factor-β1-Enriched Small-Sized Extracellular Vesicles.

Psoriasis is a common chronic inflammatory disease in which keratinocytes proliferate abnormally due to excessive immune action. Psoriasis can be associated with various comorbidities and has a significant impact on health-related quality of life. Although many systemic treatments, including biologic agents, have been developed, topical treatment remains the main option for psoriasis management. Consequently, there is an urgent need to develop topical treatments with minimal side effects and high efficacy. Mesenchymal stem cells (MSCs) exhibit excellent immune regulation, anti-inflammatory activities, and therapeutic effects, and MSC-derived extracellular vesicles (EVs) can serve as crucial mediators of functional transfer from MSCs. Therefore, this study aimed to develop a safe and easy-to-use emulsion cream for treating psoriasis using MSC conditioned media (CM) containing EVs. We developed an enhanced Wharton's jelly MSC (WJ-MSC) culture method through a three-dimensional (3D) culture containing exogenous transforming growth factor-β3. Using the 3D culture system, we obtained CM from WJ-MSCs, which yielded a higher EV production compared to that of conventional WJ-MSC culture methods, and investigated the effect of EV-enriched 3D-WJ-MSC-CM cream on psoriasis-related inflammation. Administration of the EV-enriched 3D-WJ-MSC-CM cream significantly reduced erythema, thickness, and scaling of skin lesions, alleviated imiquimod-induced psoriasiform lesions in mice, and ameliorated histopathological changes in mouse skin. The upregulated mRNA expression of inflammatory cytokines, including IL-17a, IL-22, IL-23, and IL-36, decreased in the lesions. In conclusion, we present here a new topical treatment for psoriasis using an MSC EV-enriched cream.

Co-delivery of SN38 and MEF2D-siRNA via tLyp-1-modified liposomes reverses PD-L1 expression induced by STING activation in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) exhibits an immunosuppressive tumor microenvironment, leading to a low objective response rate when immune checkpoint inhibitors (ICIs) are utilized. The cGAS-STING pathway demonstrates a powerful immune stimulatory effect, nevertheless, activation of this pathway triggers an upregulation of PD-L1, which inhibits the anti-tumor function of immune cells. The present study discovered that knockdown of MEF2D by a siRNA in H22 cells decreases the expression of PD-L1. Subsequently, tLyp-1-modified liposomes were developed for the delivery of SN38 and MEF2D-siRNA. The outcomes indicated that the modification of tLyp-1 could enhance the uptake of liposomes by tumor cells. tLip/siMEF2D/SN38 liposomes can effectively knockdown the expression of MEF2D in HCC cells and reduce the expression of PD-L1 in vitro and in vivo, thereby enhancing proliferation inhibition and apoptosis induction, and effectively suppressing the growth of tumors. SN38 treatment elevated the expression of p-TBK1 and p-IRF3 in tumor tissue, signifying the activation of the cGAS-STING pathway and facilitating the maturation of dendritic cells in vitro and in vivo. At the same time, the co-delivery of MEF2D-siRNA reduced the expression of PD-L1, thereby decreasing the quantity of M2 macrophages and myeloid-derived suppressor cells (MDSCs) in tumors, increasing the number of CD4+ T cells within the tumor, and strengthening the anti-tumor immune efficacy. In conclusion, our results suggest that tLyP-1 modified, SN38- and MEF2D siRNA-loaded liposomes have the potential for the treatment of HCC and optimize the immunotherapy of HCC via STING activation.

Cancer cell-selective induction of mitochondrial stress and immunogenic cell death by PT-112 in human prostate cell lines

PT-112 is a novel immunogenic cell death (ICD)-inducing small molecule currently under Phase 2 clinical development, including in metastatic castration-resistant prostate cancer (mCRPC), an immunologically cold and heterogeneous disease state in need of novel therapeutic approaches. PT-112 has been shown to cause ribosome biogenesis inhibition and organelle stress followed by ICD in cancer cells, culminating in anticancer immunity. In addition, clinical evidence of PT-112-driven immune effects has been observed in patient immunoprofiling. Given the unmet need for immune-based therapies in prostate cancer, along with a Phase I study (NCT#02266745) showing PT-112 activity in mCRPC patients, we investigated PT-112 effects in a panel of human prostate cancer cell lines. PT-112 demonstrated cancer cell selectivity, inhibiting cell growth and leading to cell death in prostate cancer cells without affecting the non-tumorigenic epithelial prostate cell line RWPE-1 at the concentrations tested. PT-112 also caused caspase-3 activation, as well as stress features in mitochondria including ROS generation, compromised membrane integrity, altered respiration, and morphological changes. Moreover, PT-112 induced damage-associated molecular pattern (DAMP) release, the first demonstration of ICD in human cancer cell lines, in addition to autophagy initiation across the panel. Taken together, PT-112 caused selective stress, growth inhibition and death in human prostate cancer cell lines. Our data provide additional insight into mitochondrial stress and ICD in response to PT-112. PT-112 anticancer immunogenicity could have clinical applications and is currently under investigation in a Phase 2 mCRPC study.

Prospects of vaccination against pneumococcal infection based on the asthma phenotype

According to recent studies, bronchial asthma is characterized by a wide variability of the mechanisms of occurrence and progression. This heterogeneity is caused by patterns of predominant cells and inflammatory mediators, which determine differences in immunological parameters observed in patients with certain endotypes depending on the dominant type of mediators (high and low T2 inflammation). In long-term observations, a substantial research base has been accumulated justifying the effectiveness of vaccination against pneumococcal infection in patients with asthma. The vaccination decreases the frequency of exacerbations of the disease and hospitalizations in the short and medium term. However, these studies evaluated the asthma patients as a wholesome population, and it remains unexplored whether the effect of pneumococcal vaccines on asthma differs depending on the endotype of the disease and what are the mechanisms of such a differentiated effect.The aim of this work is to present the results of recent quality studies on changes in the profile of inflammatory asthma mediators under the action of immunobiological substances based on Streptococcus pneumoniae antigens, primarily from the vaccines.Conclusion. The asthma heterogeneity can lead to different clinical outcomes in pneumococcal infection and, respectively, the clinical effects of immunization in patients differentiate according to the nature of inflammation. In other words, the uniformity of the clinical effect of vaccination against pneumococcal infection in all patients in ongoing studies may represent the combined effect of molecular mechanisms regulating the specific activity of Th1-, Th2-, Th17-, NKT-, and Treg-cells. The results of studies proving the ability of pneumococcal vaccines to modulate the Th1-, Th2-, Th17-, Treg immune response in patients with asthma contributed to increased interest in developing new immunoregulatory therapeutic agents based on S. pneumoniae antigens.

Regulation of Airway Epithelial-Derived Alarmins in Asthma: Perspectives for Therapeutic Targets.

Asthma is a chronic respiratory condition predominantly driven by a type 2 immune response. Epithelial-derived alarmins such as thymic stromal lymphopoietin (TSLP), interleukin (IL)-33, and IL-25 orchestrate the activation of downstream Th2 cells and group 2 innate lymphoid cells (ILC2s), along with other immune effector cells. While these alarmins are produced in response to inhaled triggers, such as allergens, respiratory pathogens or particulate matter, disproportionate alarmin production by airway epithelial cells can lead to asthma exacerbations. With alarmins produced upstream of the type 2 inflammatory cascade, understanding the pathways by which these alarmins are regulated and expressed is critical to further explore new therapeutics for the treatment of asthmatic patients. This review emphasizes the critical role of airway epithelium and epithelial-derived alarmins in asthma pathogenesis and highlights the potential of targeting alarmins as a promising therapeutic to improve outcomes for asthma patients.