Frontiers in Immunology最新文献

The IL-2 family, consisting of IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21, is a key regulator of the immune response. As an important endocrine and digestive organ, the function of the pancreas is regulated by the immune system. Studies have shown that each cytokine of the IL-2 family influences the occurrence and development of pancreatic diseases by participating in the regulation of the immune system. In this paper, we review the structural and functional characteristics of IL-2 family members, focus on their molecular mechanisms in pancreatic diseases including acute pancreatitis, chronic pancreatitis and pancreatic cancer, and highlight the importance of the related proteins in the regulation of immune response and disease progression, which will provide valuable insights for new biomarkers in pancreatic diseases, early diagnosis of the diseases, assessment of the disease severity, and development of new therapeutic regimens. The insights of the study are summarized in the following sections.

Background: Despite durable responses achieved with Immune Checkpoint Inhibitors (ICIs), data about optimal duration of treatment, especially in the context of adverse events, remain scarce.

Objective: To systematically review the evidence concerning the impact of treatment discontinuation with ICIs for reasons other than progressive disease (PD) on relapse rates and survival of melanoma patients.

Methods: A systematic literature search was conducted in three electronic databases until July 2024. Studies referring to melanoma patients who ceased ICIs electively (i.e. due to complete response (CR), protocol completion or patient/physician's wish) or due to treatment-limiting toxicities (TLTs) were selected. Relapse rates (RRs) post cessation, time to PD, rechallenge and disease control rate (DCR) after 2^nd course were the main outcomes. Random-effects models were preferred, and subgroup and sensitivity analyses were conducted to investigate possible sources of heterogeneity.

Results: 38 and 35 studies were included in qualitative and quantitative synthesis, respectively. From 2542 patients discontinued treatment with ICIs electively or due to TLTs, 495 experienced progression [number of studies (n)=34, RR 20.9%, 95%CI 17.1 - 24.7%, I² 85%) and higher rates were detected in patients with TLTs compared to elective discontinuation. Mean time to PD was 14.26 months (n=18, mean time 14.26, 95%CI 11.54 - 16.98, I² 93%) and was numerically higher in patients who ceased for CR compared to patients with TLTs. Treatment duration before cessation was not associated with risk and time to relapse, while mucosal melanomas and non-CR as BOR during treatment led to increased risk for relapse and shorter time to PD compared to other histologic subtypes or CR. Rechallenge with ICI resulted in 57.3% DCR and 28.6% pooled CR rates (n=22, CR rate 28.6%, 95%CI 17.1 - 40.2, I² 68%). Heterogeneity among studies was high, but subgroup analysis based on type of ICI used (anti-CTL4 and anti-PD1 inhibitor or anti-PD1 monotherapy) and type of study (RCTs or observational studies), along with sensitivity analyses did not reveal significant alterations in results.

Conclusion: Discontinuation of ICIs in patients without progression is possible. Outcomes to rechallenge with ICIs may differ depending on the reason for discontinuation, but remains a considerable option.

Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42024547792.

Immune checkpoint inhibitors (ICIs) are drugs that are being increasingly used in the field of oncology; due to their mechanism of action, they can present immune-related adverse effects (IRAEs), with various clinical manifestations, one of which is delirium. We present the case of a patient diagnosed with pleural mesothelioma that started combined palliative immunotherapy two months before admission. She was hospitalized for delirium with psychotic symptoms and a comprehensive neurological and etiological examination for this pathology was performed, revealing undetectable TSH levels, indicating the etiology of the condition as thyrotoxicosis in the context of autoimmune thyroiditis, secondary to treatment with ICIs. Symptomatic treatment with beta-blockers was initiated, leading to progressive improvement. This case brings awareness of impaired consciousness and neuropsychiatric symptoms as manifestation of IRAEs and the difficulty of their diagnosis: there may also be several other causes of impaired consciousness, so the characterization of delirium requires a multifaceted approach to determine the underlying cause, taking into account direct cancer-related complications and those stemming from the treatments received by this group of patients. Endocrinological immune-related adverse events (IRAEs), such as thyroid IRAEs, generally have a low lethality rate, do not necessarily require discontinuation of therapy, and are linked to a more favorable oncological prognosis. Conversely, neurological IRAEs, though rare, constitute a contraindication for further use of ICIs. This clinical case emphasizes the importance of the systematic study of consciousness impairment in cancer patients, and of considering multiple IRAEs that could lead to changes in oncological therapy when establishing possible etiologies.

CRISPR/Cas9-mediated genome editing has the potential to delete PD-L1 both on the cell surface and inside the cell, thereby inhibiting tumor growth and migration and overcoming immunosuppression. ZG16, with its lectin structure, can reduce PD-L1 expression on the cell surface. However, direct comparison of two approaches on PD-L1 expression in Pancreatic ductal adenocarcinoma (PDAC) cells has not yet been investigated. In this study, we established two Panc-1 cell line: one with PD-L1 knockout and another with ZG16 overexpression. Both methods promoted the polarization of tumor-associated macrophages (TAMs) to the M1 phenotype, as indicated by increased levels of the M1 marker CD11c+ in vitro and in vivo. Meanwhile, we observed a reduction in the M2 marker CD206+, upregulation of immune activation-related cytokines/chemokines, and a decrease in immunosuppressive cytokines and tumor angiogenesis factors. In summary, both PD-L1 knockout and ZG16 overexpression represent promising approaches for PDAC treatment.

Ninjurin1 (NINJ1) is initially identified as a nerve injury-induced adhesion molecule that facilitates axon growth. It is initially characterized to promote nerve regeneration and mediate the transendothelial transport of monocytes/macrophages associated with neuroinflammation. Recent evidence indicates that NINJ1 mediates plasma membrane rupture (PMR) in lytic cell death. The absence or inhibition of NINJ1 can delay PMR, thereby mitigating the spread of inflammation resulting from cell lysis and preventing the progression of various cell death-related pathologies, suggesting a conserved regulatory mechanism across these processes. Further research elucidated the structural basis and mechanism of NINJ1-mediated PMR. Although the role of NINJ1 in PMR is established, the identity of its activating factors and its implications in diseases remain to be fully explored. This review synthesizes current knowledge regarding the structural basis and mechanism of NINJ1-mediated PMR and discusses its significance and therapeutic targeting potential in inflammatory diseases, neurological disorders, cancer, and vascular injuries.

Background: Uveitis, characterized by intraocular inflammation, poses significant clinical challenges, often leading to vision impairment or blindness. Herpes Simplex Virus type 1 (HSV-1) is a major cause of virus-induced uveitis. This study aims to design a novel multi-epitope vaccine targeting HSV-1 glycoproteins B, C, D, H, and L using an immuno-informatics approach, which are essential for viral entry and pathogenesis.

Methods: The study identified epitopes for CD8+ T cells, CD4+ T cells, and B cells within the target glycoproteins. These epitopes were systematically evaluated for conservancy, immunogenicity, non-allergenicity, non-glycosylated regions, and binding affinities. A multi-epitope construct was designed, incorporating these epitopes along with an adjuvant, a PADRE sequence, and suitable linkers. In-silico immune simulations were performed to evaluate the vaccine's potential to activate both innate and adaptive immune responses. Molecular docking simulations assessed the binding interactions between the multi-epitope vaccine and Toll-like receptor (TLR-9).

Results: The selected epitopes demonstrated high conservancy, immunogenicity, and non-allergenicity. The multi-epitope construct effectively activated cytokine production, immunoglobulin secretion, and T cell responses in in-silico immune simulations. Molecular docking simulations showed strong binding interactions between the vaccine and TLR-9, suggesting enhanced antigen presentation capabilities.

Conclusion: This comprehensive immuno-informatics approach provides a precision immunotherapy strategy for uveitis by leveraging computational modeling and predictive analytics to design a multi-epitope vaccine for HSV-1. The in-silico results indicate the vaccine's potential efficacy in activating immune responses. Future experimental validation and clinical studies are necessary to confirm the safety and efficacy of this proposed vaccine in managing uveitis and preserving vision.

[This corrects the article DOI: 10.3389/fimmu.2022.853000.].

The domain of cancer treatment has persistently been confronted with significant challenges, including those associated with recurrence and drug resistance. The complement system, which serves as the foundation of the innate immune system, exhibits intricate and nuanced dual characteristics in the evolution of tumors. On the one hand, the complement system has the capacity to directly inhibit cancer cell proliferation via specific pathways, thereby exerting a beneficial anti-tumor effect. Conversely, the complement system can also facilitate the establishment of an immune escape barrier for cancer cells through non-complement-mediated mechanisms, thereby protecting them from eradication. Concurrently, the complement system can also be implicated in the emergence of drug resistance through a multitude of complex mechanisms, directly or indirectly reducing the efficacy of therapeutic interventions and facilitating the progression of cancer. This paper analyses the role of the complement system in tumors and reviews recent research advances in the mechanisms of tumor immune tolerance and drug resistance.

Background: Abdominal aortic aneurysm (AAA) is a degenerative disease with high mortality. Chronic inflammation plays a vital role in the formation of AAA. Atractylenolide-I (ATL-I) is a major bioactive component of Rhizoma Atractylodis Macrocephalae that exerts anti-inflammatory effects in various diseases. The purpose of this study is to investigate the role of ATL-I in the progression of AAA.

Methods: AAA was constructed in C57BL/6 mice by porcine pancreatic elastase (PPE)-incubation, and the diameter of the aorta was measured by ultrasound. ATL-I was administered by gavage on the second day after modeling to explore its significance in AAA. The pathological and molecular alteration was investigated by immunostaining, ELISA, qRT-PCR and Western blotting.

Results: ATL-I inhibited the dilatation of the abdominal aorta and decreased the incidence of AAA. ATL-I alleviated the infiltration of macrophages in the adventitia and reduced the levels of proinflammatory factor IL-1β and IL-6 in the aorta and circulatory system, while increasing the expression of anti-inflammatory factor IL-10. Moreover, ATL-I restrained loss of smooth muscle cells and elastic fiber degradation by suppressing MMP-2 and MMP-9 expression. Mechanistically, phospho-AMPK expression was elevated in AAA groups, and ATL-I administration suppressed its expression to improve the pathological damage of aorta.

Conclusions: ATL-I meliorated vascular inflammation by targeting AMPK signaling, ultimately inhibiting AAA formation, which provided an alternative agent for AAA treatment.

Immunodeficiency, centromeric instability, and facial anomalies syndrome (ICF) is a rare genetic disease characterized by hypogammaglobulinemia, T cell immune deficiency with age, pericentromeric hypomethylation, facial abnormalities, and intellectual disability. This study aimed to investigate the phenotype and immune function of a girl with ICF2, identify her genetic defect, and explore the potential pathogenic mechanisms of the disease. We identified a homologous deletion mutation in this girl, which involves exons 1-5 and part of introns 1 and 6 of the ZBTB24 gene (NG_029388.1: g.2831_18,995del). This ZBTB24 variant produces a severely truncated ZBTB24 protein that lacks the BTB, A-T hook and eight zinc fingers. The above changes may lead to abnormal transcriptional function of the ZBTB24 protein. Karyotype analysis showed fragile sites and entire arm deletions were detected on chromosomes 1 and 16 and triradials on chromosome 16. The novel multi-exon deletion of ZBTB24 causes immunodeficiency, severe pneumonia and centromeric instability in the patient. During the follow-up, the patient's pneumonia continued to progress despite receiving intravenous immunoglobulin (IVIG) replacement and anti-infective therapy. These results indicated that this novel multi-exon deletion variant of ZBTB24 may be the genetic etiology of ICF2. The discovery of this novel mutation expands the mutation spectrum of the ZBTB24 gene and improves our understanding of the molecular mechanisms underlying ICF.