Immunosuppressive Effects Research Articles

Evaluation of the expression of FLG, AHR and ARNT genes in the skin of patients with atopic dermatitis after phototherapy

Background: Ultraviolet irradiation of the skin can activate the cytoplasmic aryl hydrocarbon receptor AhR, which, in combination with its nuclear translocator ARNT binds to the promoter of the FLG gene encoding filaggrin, a protective skin barrier protein. This suggests that the therapeutic effect of phototherapy may be due not only to the immunosuppressive effect, but also to stimulation of filaggrin production. Aims: to evaluate the effect of ultraviolet irradiation used for various phototherapy methods on the expression levels of the FLG, AHR and ARNT genes in the skin of patients with atopic dermatitis. Materials and methods: The expression levels of the FLG, AHR and ARNT genes were determined using real-time PCR. To define the severity of the disease, the SCORAD index was calculated. Results: 76 patients with atopic dermatitis were included in the study. 37 patients underwent narrow-band phototherapy; 39 – UFA1 therapy. Both methods of phototherapy were effective. After narrow-band phototherapy, the level of expression of the FLG, AHR and ARNT genes significantly increased. After UFA1 therapy, the expression of the AHR and ARNT genes increased, and no changes in the expression of the FLG gene were observed. Conclusions: Data have been obtained indicating that the therapeutic effect of narrow-band phototherapy in atopic dermatitis may be due to stimulation of the expression of the FLG gene in the skin. The revealed changes in the expression of the AHR and ARNT genes indicate the possible involvement of their protein products AhR and ARNT in the pathogenesis of the disease.

Abstract IA10: Immune side effects in ferroptosis-targeted therapy

Abstract Ferroptosis, a regulated form of cell death driven by lipid peroxidation, has emerged as a promising strategy in cancer therapy, complementing established modalities such as chemotherapy, immunotherapy, and radiotherapy. While the mechanisms of ferroptosis are highly context-dependent, the classical approach to inducing ferroptosis involves targeting the GPX4 (glutathione peroxidase 4) pathway. GPX4 is a critical enzyme that detoxifies lipid hydroperoxides (L-OOH) by reducing them to non-toxic lipid alcohols (L-OH) using glutathione (GSH) as a cofactor, thereby preventing lipid peroxidation and ferroptotic cell death. Although targeting GPX4 effectively induces ferroptosis in cancer cells, its widespread expression in both tumor and normal cells presents challenges. Direct inhibition of GPX4 can lead to unintended immune cell death, potentially impairing antitumor immunity by reducing the activity of cytotoxic T cells and other immune effectors essential for robust immune responses. This immunosuppressive effect could undermine the therapeutic benefits of ferroptosis-targeted therapies. To overcome this limitation, alternative strategies have been explored. For instance, non-direct targeting of GPX4, such as inducing TRIM25-mediated degradation of GPX4, has shown promise in selectively killing cancer cells while sparing normal tissues and preserving immune function. This approach minimizes toxicity and maintains the activity of key immune cells, including cytotoxic T cells, enhancing the overall efficacy of ferroptosis-based treatments. Understanding the potential risks and immune-related side effects of ferroptosis-targeted therapies is critical for their successful clinical translation. Citation Format: Daolin Tang. Immune side effects in ferroptosis-targeted therapy. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr IA10

Abstract B019: Mathematical modeling-based optimization of gamma knife surgery after checkpoint blockade in melanoma brain metastases

Abstract Gamma knife radiotherapy (RT) treatment is often used as a salvage therapy after progression of melanoma brain metastasis (MBM) lesions under immune checkpoint inhibitor (ICI) blockade therapy; however, waiting until progression of nonresponsive lesions can result in significant symptomatic progression, and the toxicity of RT is greater for larger lesions as it is directly proportional to lesion volume. Robust and reliable standards for consistently maximizing the benefit of combination ICI + RT therapy remain elusive, likely in part due to the complexity of mechanistic interactions between each therapy. Addressing this clinical need will require optimizing the effects of their reported synergistic interactions such as tumor microenvironment modulation and immune activation while mitigating inhibitory effects such as immunosuppressive radiation effects. The ability to identify lesions unlikely to respond to ICI shortly after start of treatment would offer immediate clinical benefit by enabling earlier RT delivery, reduce the volume-dependent toxicities of RT, and reduce symptoms from lesion progression. To address the unmet clinical need for methods to optimize outcomes of combination ICI and RT therapy, we have developed a mechanistic mathematical model based on the biological and physical underpinnings of these complex therapies, and their interactions, which is able to describe and quantify interactions between ICI and RT and their interactions on the tumor. This builds upon our previous ICI modeling work by expanding the model based on the assumption that therapeutic outcome is not only a result of direct interaction between the treatment and disease, but is also a result of complex interplay between heterogeneous tumor populations that may be sensitive or resistant to treatment and their unique interactions with the immune system that serve to maintain or disrupt the tumor-immune equilibrium. RT further modulates this tumor-immune dynamic both by killing T cells in the tumor interior and by stimulating release of T cell activating antigens which can alter T cell activation exterior to the tumor, thereby affecting T cell recruitment into the tumor. By capturing how the complex time-dependent dynamics of tumor-immune interaction and recruitment influences – and is influenced by – transient shifts in treatment sensitive and resistant populations, our model aims to describe and quantify long-term tumor dynamics after ICI + RT therapy. This platform provides a consistent framework for systematically evaluating various proposed mechanisms underlying treatment interactions and how these may determine treatment failure or success. By applying the model to a retrospective, in-house generated melanoma brain metastasis data set, we are examining and refining our model structure with a goal of capturing a wide range of observed tumor dynamics using only clinically available data. This may lead to robust, quantitative methods to maximize treatment outcomes based on the unique characteristics of individual tumors. Citation Format: Alexander R. J. Silalahi, Caroline Chung, James W. Welsh, Zhihui Wang, Joseph D. Butner. Mathematical modeling-based optimization of gamma knife surgery after checkpoint blockade in melanoma brain metastases. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B019.

Abstract B018: GSK3β inhibition synergizes with radiation therapy to stimulate type-I interferon and anti-tumor effects in lung cancer

Abstract Radiation therapy (RT) is widely used to treat various tumor types to minimize the risk of recurrence. However, only a subset of patients experiences significant responses to RT, primarily due to inadequate immune responses within lung tumors. Therefore, there is a pressing need to develop innovative strategies to overcome tumor immunosuppression following RT. In this study, we investigated alternative mediators that could mitigate the effects of immunosuppression in lung cancer cells. We screened over 700 pharmacological inhibitors using an interferon beta-1(IFNβ1)-luciferase reporter system, identifying a group of glycogen synthase kinase 3 beta inhibitors (GSK3βi) that enhanced IFNβ1 expression. Notably, one GSK3βi agent, Kenpaullone, significantly induced IFNβ1 in multiple lung cancer cell lines. Compared to other GSK3β inhibitors, it exhibited superior synergy (over 20-fold) without inducing cellular cytotoxicity, even at high doses (30 µM). Furthermore, our syngeneic mouse models showed that GSK3βi and RT reduced tumor size more effectively than monotherapy and enhanced immunologic response in these tumors. This pharmacological-RT combination approach holds promise for improving the immunologic response to RT in lung cancer patients, potentially reducing tumor burden in those that already exhausted standard of care treatment options. Citation Format: Chen Braun Nan Li, Steven H. Lin. GSK3β inhibition synergizes with radiation therapy to stimulate type-I interferon and anti-tumor effects in lung cancer. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B018

Abstract B014: Dual checkpoint blockade mitigates the immunosuppressive effects of radiotherapy amplified by experimental liver metastasis

Abstract Background: Stereotactic Radiotherapy (RT) is commonly used to manage tumor burden and progression in metastatic cancer patients, often presenting with synchronous liver metastases (LM). Our previous work demonstrated LM is associated with poor responses to checkpoint inhibitor (CPI) and induces systemic tumor-specific immune tolerance in an immunocompetent LM murine model. RT can either stimulate or suppress immune responses, but its immunomodulatory effects and whether it can complement immunotherapy in the context of LM remain unclear. We hypothesize RT in the presence of LM may have unique systemic immunomodulatory effects and aim to measure its impact on innate and adaptive antitumor immunity. Methods: Mice were injected with MC38-Luc cells both subcutaneously (SQ) and intrahepatically to generate SQ-LM mice to mimic multiple disease sites in LM patients. A commonly used dual-SQ model was generated as tumor-site control, as it reliably produces the abscopal response with RT+CPI treatment. SQ tumor of each RT groups were treated with one ablative dose of 14Gy using an image-guided small animal irradiator. Tumor growth of both irradiated and non-irradiated tumor by in vivo imaging were recorded for the following treatment group: No treatment (no-tx), RT alone, RT+aPD-1, RT+dual-CPI (aPD-1+aCTLA-4). Additionally, NRG mice were used to rule out lymphocyte effects. Finally, innate and adaptive responses in both tumor sites were analyzed by 24-color spectral cytometry. Results: SQ RT reduced the local tumor growth compared to no-tx control. Compared to dual-SQ mice, RT-targeted to SQ tumors in the SQ-LM mice had reduced local efficacy. SQ RT paradoxically accelerated growth at the non-irradiated LM site in 3 out of 9 cases, compared to no-tx. The distant LM promoting effect from RT was reproduced in NRG mice, suggesting a T/B cell-independent pro-tumor mechanism. Combining aPD-1 to SQ RT treatment did not significantly enhance response at the LM site nor yield significant abscopal effects. However, combining dual CPI with SQ RT produced significant efficacy improvements over no-tx control at both local and abscopal sites, achieving ∼40% complete response rate. Spectral flow analysis revealed distinct immune modulation as a result RT, revealing SQ RT increased CD80/86 expression on MHC II⁺ monocytes exclusively at the SQ site and decreased ICOS⁺ and Ki67⁺ on CD8⁺ T cells at the liver tumor. In contrast, triple combination therapy enhanced ICOS⁺ CD8⁺ T cells at both sites, compared to control groups. Conclusions: RT targeting to SQ tumor in the presence of LM may inadvertently foster systemic immunosuppression through non-redundant innate immune pathways, promoting growth of non-irradiated liver tumors. However, RT+aPD-1+aCTLA-4 treatment counteracted this effect, suggesting a promising approach to overcome the adverse impact of RT in the context of LM. Data supports dual CPI therapy mitigates potential negative immune impacts from RT in patients with LM, warranting further clinical investigation. Ethics Animal study IACUC approval AN202115 by UCSF Citation Format: Han Zang, Asha Bunyan, Luke Kim, Dhruvi Mistry, Karan Bhatt, Shao Tao, James Lee. Dual checkpoint blockade mitigates the immunosuppressive effects of radiotherapy amplified by experimental liver metastasis. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B014.

Review of the mechanisms of virus-induced immunosuppression in poultry

A healthy immune system is the basis of successfully poultry farming. The industry suffers economic losses due to prolonged immunosuppression mediated by several viruses: Marek's disease virus (MDV), chicken infectious anemia virus (CIAV), infectious bursal disease virus (IBDV), reoviruses, some retroviruses as well as their associations. Two categories of causes of viral immunosuppression have been identified: apoptosis and/or necrosis of lymphoid cells and changes caused by the virus in the regulation of the immune response due to disruption of the cytokine profile. In many cases, the actual molecular interactions between virus proteins and host cells are poorly understood. Future research should focus on better understanding the interplay between viruses, immunocompetent cells, and cytokine regulation. Recent developments in the understanding of the immunotoxic and immunosuppressive effects of viruses may potentially offer a way to prevent these conditions.

Mitochondrial respiratory complex III sustains IL-10 production in activated macrophages and promotes tumor-mediated immune evasion.

The cytokine interleukin-10 (IL-10) limits the immune response and promotes resolution of acute inflammation. Because of its immunosuppressive effects, IL-10 up-regulation is a common feature of tumor progression and metastasis. Recently, IL-10 regulation has been shown to depend on mitochondria and redox-sensitive signals. We have found that Suppressor of site IIIQo Electron Leak 1.2 (S3QEL 1.2), a specific inhibitor of reactive oxygen species (ROS) production from mitochondrial complex III, and myxothiazol, a complex III inhibitor, decrease IL-10 in lipopolysaccharide (LPS)-activated macrophages. IL-10 down-regulation is likely to be mediated by suppression of c-Fos, which is a subunit of activator protein 1 (AP1), a transcription factor required for IL-10 gene expression. S3QEL 1.2 impairs IL-10 production in vivo after LPS challenge and promotes the survival of mice bearing B16F10 melanoma by lowering tumor growth. Our data identify a link between complex III-dependent ROS generation and IL-10 production in macrophages, the targeting of which could have potential in boosting antitumor immunity.

A surgical orthotopic xenograft approach with immune response for colorectal cancer research.

The high morbidity and mortality of colorectal cancer (CRC) is a major challenge in clinical practice. Although a series of alternative research models of CRC have been developed, appropriate orthotopic animal models that reproduce the specific clinical response as well as pathophysiological immune features of CRC are still lacking. In the current study, we constructed a CRC orthotopic xenograft model by implanting the tumor tubes at the colorectum of mice and monitored the model development using bioluminescence imaging. This model successfully recapitulates the clinical chemotherapy efficacy, including reduced total flux, tumor weight, and the expression of Ki67 after treatment of the first-line chemotherapy regime of CRC (FOLFOX: oxaliplatin and 5-fluorouracil/calcium folinate). The model also reproduced the immunosuppressive effect of FOLFOX, indicated by decreased infiltration of macrophages and increased Treg cells in tumor. Additionally, the orthotopic xenograft approach may be applied in immunodeficient NCG/NSG mice for constructing patient-derived xenografts, and being used in clinical precision medicine and drug evaluation. We believe the current model is a successful surgical orthotopic xenograft approach for cancer research and deserves to be popularized, which will provide a convenient and efficient platform for in-depth mechanism exploration of CRC and preclinical drug evaluation.

Long-term Metabolic Outcomes Post-Simultaneous Pancreas-Kidney Transplantation in Recipients With Type 1 Diabetes.

Simultaneous pancreas-kidney (SPK) transplantation is an effective treatment option for type 1 diabetes mellitus and concurrent end-stage kidney disease. However, the diabetogenic effects of immunosuppression can counteract the beneficial effects of sustained normoglycemia. Long-term metabolic trends that reflect cardiovascular risk are reported poorly in the literature. A total of 500 patients with type 1 diabetes mellitus receiving SPK transplants at a single center with at least 2-y follow-up were evaluated retrospectively. Metabolic parameters and allograft function were followed longitudinally, including patient and allograft survival, body mass index (BMI), lipid profile, quantitative insulin sensitivity check index, estimated glomerular filtration rate, and urinary albumin-creatinine ratio up to 10 y posttransplant. Patient survival at 1, 5, and 10 y was 97%, 92%, and 87%, and overall death-censored graft survival was 87%, 84%, and 80%, respectively. Survival remained unchanged when stratified by BMI. Compared with pretransplant measurements, BMI significantly increased at 1, 3, and 5 y posttransplant. Total cholesterol, triglycerides, and low-density lipoprotein cholesterol decreased at 10 y posttransplant, with significantly increased high-density lipoprotein cholesterol at 5 y posttransplant. Insulin sensitivity improved significantly at 10 y posttransplant but did not normalize. Urinary albumin-creatinine ratio decreased by 3 y posttransplant but increased significantly between 3 and 10 y posttransplant, although the estimated glomerular filtration rate was unchanged during this time. SPK transplantation is associated with excellent patient and graft survival. Significant long-term weight gain occurs despite improving lipid profiles and insulin sensitivity posttransplant. These data potentially reflect an overall cardiovascular burden that should be addressed in this population.

Cancer and Secretomes: HLA-G and Cancer Puzzle.

Among the mechanisms, cancer cells develop to elude immune system, immune regulation and the use of molecules that play important roles in immune escape stand out. One of these molecules, the human leukocyte antigen G (HLA-G), plays an important role in the maintenance of immune tolerance and contributes to the progression of cancer by exerting an immunosuppressive effect. By creating an immunosuppressive field in the microscopic environment of the tumor, the aberrant expression of HLA-G facilitates the evading of cancer cells from the immune system and contributes to the progression of the disease. It is important to study how HLA-Gs interact with secretome components, especially at the level of specific components, to develop treatment strategies that prevent cancer cells evading the immune system. Cancer cells may be recognized and targeted by the immune system by reducing the inhibitory effect of HLA-G on immune cells and by neutralizing tumor-promoting components of the secretome. This review focuses on the interaction of specific cancer cell secretomes and HLA-G. Here we also investigate the role of this interaction in tumor immune escape strategies.

The effect of immunosuppression on outcomes in elderly patients with community-acquired pneumonia

BackgroundThe effect of immunosuppression on clinical manifestations and outcomes was unclear in elderly patients with CAP.MethodsElderly hospitalised patients with CAP were consecutively enrolled and were divided into immunocompromised hosts (ICHs) or non-ICHs groups. Clinical manifestations, severity, and outcomes were compared. The logistic regression model was used to determine the association between immunosuppression and outcomes. The primary outcome was 30-day mortality.ResultsA total of 822 patients were enrolled, of whom 133 (16.2%) were immunocompromised. There were no differences between the two groups in vital signs, oxygenation, admission laboratory tests, need for mechanical ventilation and intensive care unit admission, except for a lower lymphocyte count in the ICH group (0.9*10^9/L, IQR 0.6–1.3*10^9/L [ICH group] vs. 1.2*10^9/L, IQR 0.8–1.7*10^9/L [non-ICH group]; p < 0.001). The 30-day mortality in ICHs was 15.8%, significantly higher than the 5.1% in non-ICHs (p < 0.001). The risk distribution of severity was similar between the two groups when assessed by CURB-65 on admission; however, the significant difference was found when assessed by PSI. Notably, in the CURB-65 low-risk group, the 30-day mortality was significantly higher in ICHs than in non-ICHs (9.7% vs. 1.1%, p < 0.001); but there was no difference between ICHs and non-ICHs in PSI low-risk group (3.7% vs. 0.6%; p > 0.05). After adjusting for age, sex, and comorbidities, immunosuppression was significantly associated with a higher risk of 30-day mortality (odds ratio 5.004, 95% CI [2.618–9.530]).ConclusionsImmunosuppression was independently associated with an increased risk of 30-day mortality. CURB-65 may underestimate the mortality risk of ICHs.

DOP116 Preclinical characterization of IMU-856, an orally available epigenetic modulator of gut barrier function and regeneration

Abstract Background A dysfunctional intestinal mucosal barrier is a key pathophysiological hallmark and driver of a broad range of gastrointestinal diseases, including inflammatory bowel disease (IBD). To date, there are no adequate treatment strategies to ameliorate impaired barrier function. IMU-856 is an orally available and systemically acting small molecule modulator of sirtuin 6 (SIRT6), a histone/non-histone protein deacetylase and transcriptional regulator that targets the restoration of intestinal barrier function and regeneration of bowel epithelium without having any direct effect on the immune system. A double-blind, randomized, placebo-controlled phase 1/1b clinical trial of IMU-856 has been completed [1]. IMU-856 was shown to be safe and well-tolerated with a benign adverse event profile and pharmacokinetics that allow once-daily dosing. In Part C, a ‘proof of concept study’ in patients with celiac disease, IMU-856 demonstrated positive effects in four key dimensions of clinical outcome: protecting gut architecture, improving patients' symptoms severity, biomarker response and enhancing nutrient absorption. Methods In the presented preclinical studies, the target specificity and effects of IMU-856 on intestinal barrier function and regeneration were elucidated by in-vitro sirtuin activity assays, transepithelial electrical resistance (TEER) assays, dextran sulphate sodium (DSS)-induced colitis mouse models and gene expression analysis (bulk RNA sequencing). Moreover, potential immune suppressive effects of IMU-856 were assessed in stimulated human peripheral blood mononuclear cells (PBMCs). Multiple biomarkers related to health of intestinal epithelium and of enteric function were also assessed in preclinical studies and in the phase 1 trial. Results IMU-856 is a highly selective and potent modulator of SIRT6. In TEER assays, IMU-856 treatment enhanced the epithelial barrier recovery of Caco-2 monolayers after a destructive cytokine challenge and modulated tight junction protein levels. IMU-856 demonstrated activity in acute DSS-induced colitis models by reducing the severity of colitis, improving the mucosal architecture and preserving functional enterocytes (upregulation of enterocyte marker genes and the plasma biomarker citrulline). No effects of IMU-856 on T-cell proliferation and cytokine secretion (interferon-g (IFN-g)) were observed in human PBMCs. Conclusion IMU-856 data indicate restoration of intestinal barrier function and promotion of physiological mucosal regeneration without direct immunosuppressive effects and may therefore offer potential for the treatment of IBD and other gastrointestinal diseases with compromised barrier function.

Antagonism of CD28 blocks allergic responses in the ovalbumin-induced asthmatic model mice.

Allergen-reactive T helper (Th) 2 cells play a pivotal role in initiating asthma pathogenesis. The absence or interruption of CD28 signaling causes significant consequences for T-cell activation, leading to reduced cell proliferation and interleukin (IL)-2 production. A novel compound, Cyn-1324, exhibits a higher binding affinity to CD28 than CD80. Thus, targeting the CD28-CD80 interaction emerges as a promising therapeutic approach for allergic asthma. However, the impact of CD28 antagonists on allergen-induced asthma remains unreported. In this study, we explored the effects of intranasally administered Cyn-1324 on airway inflammation in the ovalbumin (OVA)-induced murine allergic model. The results revealed a significant reduction in airway hyper-responsiveness (AHR), eosinophil recruitment, and cell infiltration in lung tissues, as well as decreased OVA-specific IgE in serum and Th2 cytokine levels in OVA-stimulated lymphocyte cultures. Additionally, we demonstrated the immunosuppressive effects of Cyn-1324 in vitro, including decreased T-cell proliferation and IL-2 secretion, together with increased p27kip1 expression via inhibiting the PI3K signaling pathway. Notably, Cyn-1324 not only inhibited the NF-κB pathway, but also appeared to suppress p38 activation, which is downstream of CD3 signaling, and reduced calcium-induced NFAT protein expression. These findings suggest that Cyn-1324 alleviates allergic responses by inhibiting the CD28-CD80 interaction and holds promise as an immunosuppressive agent for allergic patients.

Enhanced effect of the immunosuppressive soluble HLA-G2 homodimer by site-specific PEGylation

Human leukocyte antigen (HLA)-G is a nonclassical HLA class I molecule that has an immunosuppressive effect mediated by binding to immune inhibitory leukocyte immunoglobulin-like receptors (LILR) B1 and LILRB2. A conventional HLA-G isoform, HLA-G1, forms a heterotrimeric complex composed of a heavy chain (α1-α3 domains), β2-microglobulin (β2m) and a cognate peptide. One of the other isoforms, HLA-G2, lacks a α2 domain or β2m to form a nondisulfide-linked homodimer, and its ectodomain specifically binds to LILRB2 expressed in human monocytes, macrophages, and dendritic cells. The administration of the ectodomain of HLA-G2, designated the soluble HLA-G2 homodimer, showed significant immunosuppressive effects in mouse models of rheumatoid arthritis and systemic lupus erythematosus, presumably by binding to a mouse ortholog of LILRB2, paired immunoglobulin-like receptor B. However, the refolded soluble HLA-G2 homodimer used in these studies tends to aggregate and degrade; thus, its stability for clinical use has been a concern. In the present study, we improved the stability of the refolded soluble HLA-G2 homodimer via a site-directed PEGylation method. PEGylation at an original free cysteine residue, Cys42, resulted in increased lyophilization and thermal and serum stability. Furthermore, the PEGylated soluble HLA-G2 homodimer could better suppress atopic symptoms in mice than the non-PEGylated homodimer. These results suggest that PEGylated soluble HLA-G2 homodimers could be candidates for immunosuppressive biologics that specifically target LILRB2-positive myelomonocytic antigen-presenting cells.

Inhibition of PDT-induced PGE2 surge for enhanced photo-immunotherapy.

Nowadays, photodynamic therapy (PDT) offers a non-invasive tumor treatment with high safety profiles and minimal side effects, implying a promising clinical application for patients with malignant tumors. However, the lack of efficacy in metastasis and recurrence still notably limits its application. To solve this problem, one promising strategy is to improve the immune response activated by PDT. Unfortunately, tumor cells derived PGE2 could create immunosuppressive microenvironments and impair the function of multiple immune cells, leading to a failure of immune system activation. Moreover, our research revealed the up-regulation of Ptgs2 in tumor cells after the PDT process, which is associated with a series of pro-tumor effects, including proliferation, invasion, metastasis, apoptotic resistance, and immune evasion. Consequently, controlling the PGE2 surge induced by PDT is crucial for optimizing the efficacy of photo-immunotherapy. Therefore, we combined the regulation of the COX2-PGE2 axis with PDT. The addition of COX inhibitors (COX-Is) could improve the efficiency of PDT, reduce the immunosuppressive effect of PGE2, and help dying tumor cells activate the immune system. Herein, a tumor-targeted nano-delivery platform (FI@T-Lipo) was developed using advanced microfluidic technology. FI@T-Lipo based PDT showed a systemic therapeutic effect in triple negative breast cancer through reclaiming the anti-tumor effect of the immune system under COX2-PGE2 blockage. In a word, we developed an in-situ tumor vaccination strategy based on COX-Is enhanced PDT, which could alleviate intra-tumoral immune suppression and boost immune system activation. Our study offers a promising modality for advancing clinical treatment strategies for metastatic malignant tumors.

Recommendations of Multiple Sclerosis and Neuroimmunology Section of Polish Neurological Society and Immuno-oncology Section of Polish Society of Oncology on oncological risk in patients with multiple sclerosis undergoing immunomodulatory therapy.

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS) that is usually diagnosed between the ages of 20 and 40. Changes in the immune system also observed in cancer may suggest a higher prevalence of cancer in the MS patient population. In recent years, many highly effective immunosuppressive drugs have been introduced into disease-modifying therapy (DMT) which may be associated with a higher risk of cancer development in patients with MS. This paper presents current data on the oncological risk of individual drugs. In addition, it provides recommendations on the management for qualifying for DMT and monitoring the safety of the therapy from anoncological perspective.

Regulation of Stress-Induced Immunosuppression in the Context of Neuroendocrine, Cytokine, and Cellular Processes.

Understanding the regulatory mechanisms of stress-induced immunosuppression and developing reliable diagnostic methods are important tasks in clinical medicine. This will allow for the development of effective strategies for the prevention and treatment of conditions associated with immune system dysfunction induced by chronic stress. The purpose of this review is to conduct a comprehensive analysis and synthesis of existing data on the regulatory mechanisms of stress-induced immunosuppression. The review is aimed at identifying key neuroendocrine, cytokine, and cellular processes underlying the suppression of the immune response under stress. This study involved a search of scientific literature covering the neuroendocrine, cellular, and molecular mechanisms of stress-induced immunosuppression regulation, as well as modern methods for its diagnosis. Major international bibliographic databases covering publications in biomedicine, psychophysiology, and immunology were selected for the search. The results of the analysis identified key mechanisms regulating stress-induced immunosuppression. The reviewed publications provided detailed descriptions of the neuroendocrine and cytokine processes underlying immune response suppression under stress. A significant portion of the data confirms that the activation of the hypothalamic-pituitary-adrenal (HPA) axis and subsequent elevation of cortisol levels exert substantial immunosuppressive effects on immune cells, particularly macrophages and lymphocytes, leading to the suppression of innate and adaptive immune responses. The data also highlight the crucial role of cortisol and catecholamines (adrenaline and noradrenaline) in initiating immunosuppressive mechanisms under chronic stress.

A Peptide Nanoregulator Enriched at the Endoplasmic Reticulum for Boosting Fractionated Radiotherapy‐Mediated Antitumor Immune Response

AbstractFractionated radiotherapy (FRT), typically delivering low‐dose radiation of 2 Gy per fraction, has been used as the main clinical treatment regimen for various tumors. However, its therapeutic efficacy is severely hindered by inadequate pro‐immunogenic effect and ionizing radiation‐induced immunosuppression. Herein, a peptide nanoregulator (SPER‐NO‐Ind) is constructed from self‐assembling peptides that can enrich nitric oxide (NO) at the endoplasmic reticulum (ER) and inhibit indoleamine 2,3‐dioxygenase (IDO) to enhance FRT‐mediated antitumor immunity and reinforce treatment outcomes. SPER‐NO‐Ind triggered S‐nitrosylation of the ryanodine receptor by ER‐specific enrichment of NO, triggering the release of Ca2+ within ER and induction of robust ER stress. The combination of 2 Gy γ‐radiation with SPER‐NO‐Ind induced intense immunogenic cell death (ICD) in ER‐stressed 4T1 cells. Furthermore, this nanoregulator inhibited IDO and decreased kynurenine production, reversing FRT‐induced immunosuppressive effects. The combined application of FRT and SPER‐NO‐Ind demonstrated superior efficacy in suppressing breast tumor growth, amplifying abscopal effects, and inhibiting metastasis in mice. The SPER‐NO‐Ind treatment achieved a 40% decrease in the total radiation dose while securing equivalent tumor suppression efficacy. Collectively, the work presents a facile approach to augment the efficacy of fractionated radiotherapy for tumors, opening up a new way to enhance the antitumor immune response of radiotherapy.

Sinomenine attenuates uremia vascular calcification by miR-143-5p

Vascular calcification is considered to be a killer of the cardiovascular system, involved inflammation and immunity. There is no approved therapeutic strategy for the prevention of vascular calcification. Sinomenine exhibited anti-inflammatory and immunosuppressive effects. Objective of this study was to investigate the effect of sinomenine in vascular calcification and its potential molecular mechanism. Adenine-induced uremic rats were constructed and administrated with sinomenine. Optical clearing of aortas, alizarin red staining, von Kossa staining, calcification quantification, micro-CT analyses of vascular calcification were performed to analyze calcification in aortas. Administration of 40 mg/kg/d sinomenine effectively alleviated vascular calcification in uremic rats. The miRNA sequencing revealed differentially expressed miRNAs in aortas and bioinformatic analysis assisted with miRNA screening. We screened 9 differential expressed miRNAs and their predicted target genes. By qRT-PCR, we validated that the expression of rno-miR-143-5p was corresponding to our prediction. Sinomenine inhibited vascular smooth muscle cells (VSMCs) calcification, accompanied with miR-143-5p upregulation. MiR-143-5p mimic decreased VSMCs calcification in high phosphate condition. On the contrary, miR-143-5p inhibitor increased VSMCs calcification in high phosphate condition, which was inhibited by sinomenine. In chronic kidney disease patients with vascular calcification, the expression level of circulating miR-143-5p was lower than those without vascular calcification. Sinomenine significantly inhibited vascular calcification in VSMCs and uremic rat. MiR-143-5p was one of the collection of miRNAs modified by sinomenine in vascular calcification. Reduction of miR-143-5p in VSMCs was not only a concomitant phenomenon in pro-calcification condition but also contribute to VSMCs calcification. Circulating miR-143-5p was supposed to be a potential biomarker for vascular calcification in chronic kidney disease patients. In conclusion, sinomenine effectively alleviated vascular calcification, which was attributed to miR-143-5p regulation partly.

‘Sneaky’ uninflamed oesophageal candidiasis: morphological clues and comparison with candidiasis associated with inflammation

AimsCandida esophagitis is usually readily identified on routine H&E-stained sections as the infection typically presents with prominent acute inflammation as a clue to search for organisms. However, in some cases,...