Immune Agents Research Articles

CD19-Targeting CAR T Cells for Myositis and Interstitial Lung Disease Associated With Antisynthetase Syndrome

Autoimmune disorders can affect various organs and if refractory, can be life threatening. Recently, CD19-targeting-chimeric antigen receptor (CAR) T cells were efficacious as an immune suppressive agent in 6 patients with refractory systemic lupus erythematosus and in 1 patient with antisynthetase syndrome. To test the safety and efficacy of CD19-targeting CAR T cells in a patient with severe antisynthetase syndrome, a complex autoimmune disorder with evidence for B- and T-cell involvement. This case report describes a patient with antisynthetase syndrome with progressive myositis and interstitial lung disease refractory to available therapies (including rituximab and azathioprine), who was treated with CD19-targeting CAR T cells in June 2022 at University Hospital Tübingen in Tübingen, Germany, with the last follow-up in February 2023. Mycophenolate mofetil was added to the treatment to cotarget CD8+ T cells, hypothesized to contribute to disease activity. Prior to treatment with CD19-targeting CAR T cells, the patient received conditioning therapy with fludarabine (25 mg/m2 [5 days before until 3 days before]) and cyclophosphamide (1000 mg/m2 [3 days before]) followed by infusion of CAR T cells (1.23×106/kg [manufactured by transduction of autologous T cells with a CD19 lentiviral vector and amplification in the CliniMACS Prodigy system]) and mycophenolate mofetil (2 g/d) 35 days after CD19-targeting CAR T-cell infusion. The patient's response to therapy was followed by magnetic resonance imaging of the thigh muscle, Physician Global Assessment, functional muscle and pulmonary tests, and peripheral blood quantification of anti-Jo-1 antibody levels, lymphocyte subsets, immunoglobulins, and serological muscle enzymes. Rapid clinical improvement was observed after CD19-targeting CAR T-cell infusion. Eight months after treatment, the patient's scores on the Physician Global Assessment and muscle and pulmonary function tests improved, and there were no detectable signs of myositis on magnetic resonance imaging. Serological muscle enzymes (alanine aminotransferase, aspartate aminotransferase, creatinine kinase, and lactate dehydrogenase), CD8+ T-cell subsets, and inflammatory cytokine secretion in the peripheral blood mononuclear cells (interferon gamma, interleukin 1 [IL-1], IL-6, and IL-13) were all normalized. Further, there was a reduction in anti-Jo-1 antibody levels and a partial recovery of IgA (to 67% of normal value), IgG (to 87%), and IgM (to 58%). CD19-targeting CAR T cells directed against B cells and plasmablasts deeply reset B-cell immunity. Together with mycophenolate mofetil, CD19-targeting CAR T cells may break pathologic B-cell, as well as T-cell responses, inducing remission in refractory antisynthetase syndrome.

T-cell redirecting bispecific antibodies in multiple myeloma: Current landscape and future directions.

T-cell engaging bispecific antibodies (BsAbs) have substantial activity in heavily pretreated patients with multiple myeloma (MM). The overall response rate obtained with B-cell maturation antigen (BCMA)-targeting BsAbs is approximately 60%-70%, including a high proportion of patients achieving very good partial response or complete response. Comparable efficacy is seen with BsAbs targeting GPRC5D or FcRH5. Cytokine release syndrome is frequently observed with BsAb treatment, but mostly during the step-up doses and the first full dose. Early intervention with IL-6 receptor blocking antibodies (e.g., tocilizumab) prevents escalation to severe manifestations. Infections are also common during treatment and related to the extent of exposure to immune suppressive anti-MM agents, as well as development of hypogammaglobulinemia due to elimination of normal plasma cells, and probably because of T-cell exhaustion resulting from continuous BsAb-mediated T-cell activation. Adequate monitoring for infections and institution of infectious prophylaxis are essential. Patients treated with GPRC5D-targteing BsAbs often develop skin and nail disorders and loss of taste, which is likely related to GPRC5D expression in cells that produce hard keratin. Currently ongoing studies are aiming at further improving these results by evaluating BsAbs in combination with other drugs, such as immunomodulatory agents and anti-CD38 antibodies, as well as the application of BsAbs in earlier lines of therapy, including patients with newly diagnosed disease. We expect that the outcomes of patients with MM will further improve by the introduction of this novel type of T-cell immunotherapy.

Nomogram Based on Inflammatory Factor to Predict Therapeutic Response of Thrombocytopenia in Patients with Primary Sjögren's Syndrome.

Thrombocytopenia is a common manifestation of blood system involvement in primary Sjögren's syndrome (pSS) patients, and the treatment approach involves glucocorticoids and immune agents. However, a proportion of patients do not respond well to this therapy and failed to achieve remission. Accurate prediction of therapeutic response in pSS patients with thrombocytopenia is of great significance for improving the prognosis. This study aims to analyze the influencing factors of no remission to treatment in pSS patients with thrombocytopenia and establish an individualized nomogram to predict the treatment response of patients. The demographic data, clinical manifestations and laboratory examinations of 119 patients with thrombocytopenia pSS in our hospital were retrospectively analyzed. According to the 30-day treatment response, patients were divided into remission group and non-remission group. Logistic regression was used to analyze the influencing factors related to the treatment response of patients, and then a nomogram was further established. The discriminative ability and clinical benefit of the nomogram were evaluated by receiver operating characteristic (ROC) curve, calibration chart and decision curve analysis (DCA). After treatment, there were 80 patients in the remission group and 39 in the non-remission group. Comparative analysis and multivariate logistic regression analysis identified hemoglobin (P=0.023), C3 level (P=0.027), IgG level (P=0.040), and bone marrow megakaryocyte counts (P=0.001) as independent predictors of treatment response. The nomogram was constructed based on the above four factors, and the C-index of the model was 0.882 (95% CI 0.810-0.934). The calibration curve and DCA proved that the model has better performance. The nomogram incorporating hemoglobin, C3 level, IgG level, and bone marrow megakaryocyte counts could be used as an auxiliary tool to predict the risk of treatment non-remission in pSS patients with thrombocytopenia.

Efficacy and safety of combining PD-1 blockage and human papillomavirus vaccine for patients with relapsed/refractory advanced cervical cancer.

5530 Background: The prognosis for patients with relapsed/refractory advanced cervical cancer is dismal with a 5-year survival rate of 17%. Limited treatment options were available including platin based therapy, antiangiogenic therapy and immune therapy. Immune checkpoint blockage with anti-programmed cell death 1 (PD-1) antibodies had an overall response rate of 17% among a minority of patients. Recently a phase II study showed human papillomavirus (HPV) 16 vaccination amplified PD-1 antibodies in incurable HPV16 positive cancer with an ORR of 33%. But the study enrolled majority were oropharyngeal cancer patients (92%). Here, we designed and conducted phase II clinical trial to assess the efficacy and safety of combining anti-PD-1 antibody and HPV vaccination for patients with relapsed/refract cervical cancer. Methods: In this single-arm, single-center phase II clinical trial, patients with relapsed/refract cervical cancer were registered (NCT04096911) and enrolled from Dec, 2019 to Dec, 2022 in Department of Oncology, Northern Jiangsu People's Hospital, Yangzhou, China. All patients received prior radiation therapy and had at least one or more lines of therapies. Duration of follow up for censored patients was 36 months. The recombinant human papillomavirus quadrivalent vaccine (0.5ml) was given subcutaneously on day 0, third month, and 6th month. Anti-PD-1 antibody, 200mg was given intravenously every 3 weeks starting on day 1 for up to 2 years. Results: As of Dec 21, 2022, thirteen patients were enrolled in the trial. The median age was 55 years (range, 52 to 83 years). The overall response rate was 69.2%. Disease control rate was 84.9%. Median duration of response was 7.07 months (95%CI, 1.94 to 15.8 month). Six patients achieved complete response. Median overall survival was 13.96 month. No grade 3 and 4 toxicity occurred. Conclusions: Our study was the first clinical trial using HPV vaccine as therapeutic agent in advance cervical cancer treatment. Up to date, immunotherapy along in cervical cancer had limited response rate less than 20% and the combination therapies was less than 40%. In our study, the overall response of 69.2%, disease control rate of 84.9% and median overall survival of 13.96 months were significantly higher compared with anti-PD-1 antibody alone or any current available regiment combinations in relapsed/refract advance cervical cancer patients. We also found synergistic effect of T cell and B cell plays an important role in our study. It appears neoantigen associated with tumor was easier to initiate immune response in cervical cancer patients. This is the first time to show employing combined immune therapeutic agents only is a novel effective clinical strategy in relapsed/refract advance cervical cancer. Clinical trial information: NCT04096911 .

Subclinical atherosclerosis in Behcet's disease and its inverse relation to azathioprine use: an updated meta-analysis.

To evaluate the intima media thickness of carotid arteries (IMT) and its clinical, laboratory and treatment correlates in Behcet's disease (BD). Systematic search of EMBASE and PubMed databases from January 2016 to October 2022; we employed random effect meta-analyses for continuous outcomes and Peto's odds ratio for rare events. The meta-analysis included 36 case control studies: the IMT was greater in BD (n = 1103) than in controls (n = 832) (p < 0.0001) with wide heterogeneity (I2 = 86.9%); a sensitivity analysis that included mean age of BD participants, gender, disease duration and activity, atherogenic index of plasma, blood pressure, C-reactive protein, ethnicity, smoking status, anti-inflammatory and immune suppressive agents, revealed that male gender, mean age of participants and azathioprine use (the latter two in inverse fashion) partly explained the heterogeneity variance (p = 0.02, p = 0.005, and p = 0.01). The IMT was greater in vascular (n = 114) than in non-vascular BD (n = 214) (p = 0.006). BD patients (n = 782) had a greater pooled prevalence of carotid plaques than controls (n = 537) (13.1% vs. 2.97%, p < 0.0001). Subclinical carotid artery atherosclerosis represents a vascular feature of BD, independently of the traditional cardiovascular risk factors. The inverse correlations between IMT, age and azathioprine use suggest that thicker carotid arteries at disease onset eventually regress with immune suppressive treatment: this assumption needs verification on adequately designed clinical trials.

Cryoablation and Immunotherapy: An Enthralling Synergy for Cancer Treatment

As less invasive options for surgical tumor removal, minimally invasive ablative techniques have gained popularity. Several solid tumors are being treated with cryoablation, a non-heat-based ablation technique. Cryoablation data in comparison over time demonstrates better tumor response and faster recovery. Combining cryosurgery with other cancer therapies has been explored to improve the cancer-killing process. Cryoablation with the combination of immunotherapy, results in a robust and efficient attack on the cancer cells. This article focuses on investigating the ability of cryosurgery to create a strong antitumor response when combined with immunologic agents resulting in a synergetic effect. To achieve this objective, we combined cryosurgery with immunotherapy using Nivolumab and lpilimumab. Five clinical cases of lymph node, lung cancer, bone, and lung metastasis were followed and analyzed. In this series of patients, percutaneous cryoablation and addressing immunity agents were technically feasible. In the follow-ups, there appeared to be no radiological evidence of new tumor development.

Presence of immune factors in freshwater mussel (Hyriopsis cumingii) entails autologous serum an essential component in the culture of mantle cells.

Mussel cell culture is a challenging problem and serum serves a crucial biological role in cell culture as an autologous supply and an immunizing agent. In this study, the biology (calcium ions, total protein, pH, and osmotic pressure) of fetal bovine serum (FBS) and Hyriopsis cumingii serum (HCS) was investigated, and the development of Hyriopsis cumingii (H. cumingii) mantle cells in HCS and FBS systems was examined. The results showed that total protein, calcium ions, and osmotic pressure varied significantly (p<0.05). The activity of mantle cells was superior in the HCS culture system to that in the FBS culture system. The label-free technique was used to distinguish the two serum proteins to investigate the supportive effect of autologous serum on cell culture. These were examined for 109 unique proteins and 35 particular HCS proteins. Most differentially expressed proteins (DEPs) were involved in immune response, cell differentiation, and calcium ion binding. Furthermore, immune factors such as HSP, CALR, APOB, C3 were identified with significant differences. HSP was significantly more present in HCS than in FBS as an endogenous protective protein that regulates immune system function, cell differentiation, transport, and activity regulation. Parallel reaction monitoring (PRM) analysis was carried out to validate the expression levels of 19 DEPs, indicating high reliability of the proteomic results. This study reveals the important role of immune factors in mussel cell culture, providing a theoretical basis for explaining the applicability of autologous serum in cell culture. It is also helpful in improving the cell culture conditions of mussels.

Protein system of bacillus anthracis antigens

In our research work, we have considered the structures of some anthrax antigens, their design and functions, as well as the genetic apparatus encoding them. The study is of interest to those practicing microbiologists and researchers whose area of interest includes knowledge of the regulation of infection processes and subsequent transformations of Bacillus anthracis spores in the host organism. Pathways for the expression of B. anthracis pathogenic genes, the factors influencing them, as well as ways to use patterns in gene expression to increase the immunization in experimental animals by combining various experimental vaccines, which are currently used in preventive practice in different countries of the world and in particular in the Russian Federation, are considered in detail herein. In addition, the article may be of interest to scientists and researchers conducting research in the field of creating new immunizing agents based either on the anthrax genome or some parts thereof.

Intestinal Behcet's Disease: A Review of the Immune Mechanism and Present and Potential Biological Agents.

Behcet's disease (BD) is a chronic and recurrent systemic vasculitis involving almost all organs and tissues. Intestinal BD is defined as BD with predominant gastrointestinal involvement, presenting severe complications such as massive gastrointestinal hemorrhage, perforation, and obstruction in some cases. To some extent, intestinal BD is classified as a member of inflammatory bowel disease (IBD), as it has a lot in common with classical IBD including Crohn's disease (CD) and ulcerative colitis (UC). Certainly, the underlying pathogenesis is not the same and dysregulation of immune function is believed to be one of the main pathogeneses in intestinal BD, although the etiology has not been clear up to now. Biological agents are an emerging category of pharmaceuticals for various diseases, including inflammatory diseases and cancers, in recent decades. Based on the deep understanding of the immune mechanism of intestinal BD, biological agents targeting potential pathogenic cells, cytokines and pathways are optimized options. Recently, the adoption of biological agents such as anti-tumor necrosis factor agents has allowed for the effective treatment of patients with refractory intestinal BD who show poor response to conventional medications and are faced with the risk of surgical treatment. In this review, we have tried to summarize the immune mechanism and present potential biological agents of intestinal BD.

An immune-based multi-agent system for flexible job shop scheduling problem in dynamic and multi-objective environments

In this paper, a biological immune-based multi agent system (IMAS) is developed to overcome the multi-objectivity and dynamicity of the multi-objective dynamic flexible job shop scheduling (MODFJSS) problem. In modeling the MODFJSS problem, four objectives, i.e., makespan, total weighted tardiness, maximal machine workload, and schedule stability, are considered for simultaneous optimization. In the proposed IMAS architecture, immune agents are coordinated to identify the environment, generate a set of non-dominated schedules, and select a utility optimal schedule. In addition, these agents have the ability of self-adaptation and flexible coordination to adapt to the environment of MODFJSS problem. The performance of the proposed method was evaluated on dynamic versions of the five commonly used benchmark instance sets in comparison with three state-of-the-art algorithms. The obtained results showed that the proposed IMAS outperformed the competitors in most of the experiments conducted in this study.

Antiapoptotic and anticoagulant effects of camel milk and camel urine in methotrexate-induced hepatotoxicity

ABSTRACT Methotrexate (MTX) is widely used chemotherapeutic and immune suppressant agent. Hepatotoxicity is a common side effect of chronic MTX therapy. This study investigated the hepatoprotective properties of camel milk (CM) and camel urine (CU) in hepatotoxicity induced by intraperitoneal injection of MTX 20 mg/kg. The MTX-intoxicated animals showed elevated serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, fasting blood glucose (FBG), liver DNA fragmentation marker (DFF-40), and serum and liver cytokeratin (CK-18), decreased serum proteins, albumin, fibrinogen, and total antioxidant capacity (TAC). Decreased antithrombin (AT) was associated with prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT). Treatment with CM and CU for four weeks decreased the liver enzymes, FBG, DFF-40, and CK-18 levels and increased total proteins, albumin, fibrinogen, and TAC. However, the changes in AT, PT, and APTT persisted. CM and CU showed promising abilities to counteract MTX hepatotoxicity and they exerted cytoprotective, antiapoptotic, antioxidative, antihyperglycemic, and antithrombotic effects.

Perception and preference of health care providers regarding protective role of immunity boosters against Covid -19

Covid -19 caused by a virus to which the people with low immunity response are being affected. Immune boosters play a vital role in protecting human being from various infective organism. The immune boosters include vitamins, minerals, antioxidants, probiotics etc. Indian Government gave emphasis on improving immunity in March 2020. At That time many people started using immunity booster agents. : To study perception and preference of medical teachers about immunity booster agents against Covid -19. A questionnaire based cross sectional study was conducted among medical teachers. Questionnaire was framed in Google form and circulated in social media.Data was noted from excel sheet derived through google form and results were calculated in frequency and percentage, mean &amp;SD. 78% participants were aware about immune boosting agents in initial period of Covid and highest used immune booster agent was Kadha (98%). Participant opined that source of information during this Covid period were Government &amp; WHO guidelines (15%), TV/ newspaper (50%) and social media (41%). Most preferred and convenient to take immunity booster agent was fruits (67%). Reason for high search and use of immunity boosters is that in initial stage of Covid- 19 pandemic, there was theat to life especially in first and second wave of Covid. Along with immune boosters, diet, sleep, exercise and stress reduction are some of the most recommended measures. In present study highest used immune booster agent was Kadha. Allopathic, Ayurvedic and Homeopathic medicine were used as immunity booster agent.

Immune characteristics and genetic markers of esophageal cancer by single-cell analysis: implications for immunotherapy.

Esophageal cancer (EC) is one of the most common cancers worldwide. The prognoses for patients with the same stage of EC can vary substantially. The progress of single-cell analysis technology has furthered the understanding of tumor heterogeneity. This paper aimed to apply single-cell analysis to explore the characteristics of the tumor environment of EC and provide a basis for personalized treatment. The latest gene expression data and clinical follow-up information of single-cell sequencing results of EC samples were downloaded from The Cancer Genome Atlas (TCGA) Genomic Data Commons (GDC) Application Programming Interface (API). A differential gene function analysis of the immune infiltration signature agents in the tumor microenvironment (TME) was performed using bioinformatics analytical methods, and potential molecular targets were sought. We identified specific cell subsets in the EC and paracancerous samples, including panel cells, natural killer (NK) cells, exhausted cluster of differentiation (CD)8+ T cells, CD8+ memory T (Tcm) cells, and effector memory T (Tem) cells, including B cell enrichment in the cancer samples. Differences were detected between B cells and monocytes in stage II and III tumors, which may be related to RNA transcription and degradation. The CXCL8 protein was identified as a valid potential prognostic marker. Cell groups with homogenous cell surface markers exhibit intercellular variations that exert a considerable effect on cell function. Our study will contribute to the understanding of the TME and cellular heterogeneity in EC patients and serve as a valuable resource for in-depth exploration of the pathogenesis of EC and the identification of potential therapeutic targets in the future.

A Lesson of Immunosuppression in Renal Transplant: Retreat or Hold?

Background: Aiming at understanding whether there are cases of near-tolerance among long-term surviving kidney transplant recipients in our center, or even operant tolerance can be attempted based on their immune status, we analyzed changes of immune cell subsets and cytokines in various groups, and evaluated immune status of long-term survival recipients. Methods: A real-world, observational, retrospective cohort study was conducted in our hospital. Twenty-eight long-term recipients were selected as study subjects, 15 recent postoperative stable recipients, and 15 healthy subjects as controls. T and B lymphocyte subsets, MDSCs, and cytokines were detected and analyzed. Results: Treg/CD4 T cells, total B and B10 cells in long-term and recent renal recipients were lower than healthy controls (HC). The level of IFN-γ and IL-17A in long-term survival patients was obviously higher than that in recent postoperative stable recipients and HC, while TGF-β1 level was significantly lower in long-term survival group than in short-term postoperative group and HC. Notably, compared with short-term recipients, it has been found that the IL-6 level in both positive and negative HLA groups were obviously lower (all P<0.05). In the long-term survival group, 43% of recipients were positive for urinary protein and 50% were positive for HLA antibody. Conclusion: This "real-world" study validates the findings of real status of long-term survival recipients observed in clinical trials. Contrary to a state of proper tolerance as expected, the group recipients in long-term survival were accompanied by the increased indicators of immune response, while those related to immune tolerance were not significantly increased. Long-term survival recipients with stable renal function may be in an immune equilibrium state where immunosuppression and rejection coexist under the action of low-intensity immune agents. If immunosuppressive agents are reduced or even removed, rejection may occur.

Development of modern immunization agent against bovine papillomavirus type 1 infection based on BPV1 L1 recombinant protein.

Bovine papillomavirus type 1 L1 protein was produced in a baculovirus expression system and purified as virus-like particles (VLPs) by affinity chromatography using lectins. The morphological integrity of VLPs was confirmed by electron microscopy. Differences between the two detected variants were deciphered by mass spectrometry of peptides (MALDI-TOF). Mice were immunized with purified VLPs in doses of 10, 25, or 50 μg in combination with 1% saponin and 15% alhydrogel per dose as adjuvants. Analysis of the humoral immune response revealed increased levels of specific antibodies detected 3 weeks after the first immunization in all groups of animals. This was further significantly increased by the booster applied 3 weeks after the first dose, with the best immune response in a group of mice immunized by the largest dose of antigen. BPV1 L1 VLPs purified by affinity chromatography using lectins could be used for prophylactic immunization in veterinary medicine.

Multiagent Intratumoral Immunotherapy Can Be Effective in A20 Lymphoma Clearance and Generation of Systemic T Cell Immunity

The use of immunotherapies has shown promise against selective human cancers. Identifying novel combinations of innate and adaptive immune cell-activating agents that can work synergistically to suppress tumor growth and provide additional protection against resistance or recurrence is critical. The A20 murine lymphoma model was used to evaluate the effect of various combination immunotherapies administered intratumorally. We show that single-modality treatment with Poly(I:C) or GM-CSF-secreting allogeneic cells only modestly controls tumor growth, whereas when given together there is an improved benefit, with 50% of animals clearing tumors and surviving long-term. Neither heat nor irradiation of GM-CSF-secreting cells enhanced the response over use of live cells. The use of a TIM-3 inhibitory antibody and an OX40 agonist in combination with Poly(I:C) allowed for improved tumor control, with 90% of animals clearing tumors with or without a combination of GM-CSF-secreting cells. Across all treatment groups, mice rejecting their primary A20 tumors were immune to subsequent challenge with A20, and this longstanding immunity was T-cell dependent. The results herein support the use of combinations of innate and adaptive immune activating agents for immunotherapy against lymphoma and should be investigated in other cancer types.

Egg Yolk Antibody for Passive Immunization: Status, Challenges, and Prospects.

The immunoglobulin Y (IgY) derived from hyperimmune egg yolk is a promising passive immune agent to combat microbial infections in humans and livestock. Numerous studies have been performed to develop specific egg yolk IgY for pathogen control, but with limited success. To date, the efficacy of commercial IgY products, which are all delivered through an oral route, has not been approved or endorsed by any regulatory authorities. Several challenging issues of the IgY-based passive immunization, which were not fully recognized and holistically discussed in previous publications, have impeded the development of effective egg yolk IgY products for humans and animals. This review summarizes major challenges of this technology, including in vivo stability, purification, heterologous immunogenicity, and repertoire diversity of egg yolk IgY. To tackle these challenges, potential solutions, such as encapsulation technologies to stabilize IgY, are discussed. Exploration of this technology to combat the COVID-19 pandemic is also updated in this review.

Anterior gradient-2 regulates cell communication by coordinating cytokine-chemokine signaling and immune infiltration in breast cancer.

Anterior gradient-2 (AGR2) is crucial to breast cancer progression. However, its role in the tumor immune microenvironment remains unclear. RNA sequencing expression profiles and associated clinical information were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus databases, respectively. The AGR2 expression patterns were verified using clinical samples of breast cancer. Based on single-cell transcriptomic data, AGR2 expression patterns were identified and cell communication analysis was carried out. Furthermore, the roles of AGR2 in breast tumor progression were explored by a series of functional experiments. We found that DNA methylation was an important mechanism for regulating the expression patterns of AGR2. Patients with AGR2 low expression displayed an immune "hot" and immunosuppressive phenotype characterized by high abundance of tumor immune cell infiltration and increased enrichment scores for transforming growth factor-β (TGF-β) and epithelial-mesenchymal transition pathways, whereas patients with AGR2 high expression showed an opposite immunologic feature with a lack of immune cell infiltration, suggestive of an immune "cold" and desert phenotype. Moreover, single-cell analysis further revealed that AGR2 in malignant cells alters cell-cell interactions by coordinating cytokine-chemokine signaling and immune infiltration. Notably, two immunotherapy cohorts revealed that AGR2-coexpressed genes could serve as prognostic indicators of patient survival. In conclusion, AGR2 could promote breast cancer progression by affecting the tumor immune microenvironment. Patients with AGR2 low expression could be suitable for combination treatment with immune checkpoint inhibitor agents and TGF-β blockers. Therefore, this study provides a theoretical foundation for developing a strategy for personalized immunotherapy to patients with breast cancer.

Quinolinate promotes macrophage-induced immune tolerance in glioblastoma through the NMDAR/PPARγ signaling axis

There has been considerable scientific effort dedicated to understanding the biologic consequence and therapeutic implications of aberrant tryptophan metabolism in brain tumors and neurodegenerative diseases. A majority of this work has focused on the upstream metabolism of tryptophan; however, this has resulted in limited clinical application. Using global metabolomic profiling of patient-derived brain tumors, we identify the downstream metabolism of tryptophan and accumulation of quinolinate (QA) as a metabolic node in glioblastoma and demonstrate its critical role in promoting immune tolerance. QA acts as a metabolic checkpoint in glioblastoma by inducing NMDA receptor activation and Foxo1/PPARγ signaling in macrophages, resulting in a tumor supportive phenotype. Using a genetically-engineered mouse model designed to inhibit production of QA, we identify kynureninase as a promising therapeutic target to revert the potent immune suppressive microenvironment in glioblastoma. These findings offer an opportunity to revisit the biologic consequence of this pathway as it relates to oncogenesis and neurodegenerative disease and a framework for developing immune modulatory agents to further clinical gains in these otherwise incurable diseases.

Immunizing customers against negative brand-related information

In today’s connected market, brands are more likely than ever to face negative press that can put their customer relationships to the test. Building and fortifying positive aspects of the brand-customer relationship (such as brand commitment, brand love and self-brand connections) may ward off some of the impact of negative information on customers, but this does not always provide full protection. Even customers who love a brand can turn against it when negative information enters the picture. Considering this, the current study provides an exploratory investigation into a new way to build up customer resilience that would otherwise not be formed simply by strengthening positive attributes of the customer-brand relationship. It argues that brands can strengthen their customers’ immunity to negative brand-related information by using an immunity metric (i.e., merely asking customers to reflect on their immunity makes them more resilient to actual negative information in the future). The construct of immunity has the dual benefit of being diagnostic of relationship strength, as well as acting as an immunizing agent. We test this effect and the process underlying it using three pilot studies, three multi-method studies, and interviews with customers and managers across different contexts. By doing so, the study establishes the theoretical and practical value of customer immunity to negative information and makes critical conceptual and pragmatic contributions to the existing body of customer research.