Frontiers in Immunology最新文献

Background: Select patients with relapsed/refractory aggressive B cell lymphoma may benefit from bridging radiation (bRT) prior to anti-CD19-directed chimeric antigen receptor T cell therapy (CAR-T). Here, we examined patient and treatment factors associated with outcomes and patterns of failure after bRT and CAR-T.

Methods: We retrospectively reviewed adults with diffuse large B-cell lymphoma (DLBCL) who received bRT prior to axicabtagene ciloleucel, tisagenlecleucel, or lisocabtagene maraleucel between 11/2017-4/2023. Clinical/treatment characteristics, response, and toxicity were extracted. Survival was modeled using Kaplan-Meier or Cox regression models for events distributed over time, or binary logistic regression for disease response. Fisher's Exact Test or Mann-Whitney U methods were used.

Results: Of 51 patients, 25.5% had bulky disease and 64.7% had Stage III/IV disease at the time of RT. Comprehensive bRT alone to all disease sites was delivered to 51% of patients, and 29.4% were additionally bridged with systemic therapy. Median follow-up was 10.3 months (95% CI: 7.7-16.4). Overall response rate (ORR) was 82.4% at 30 days post-CAR-T infusion. Median overall survival (OS) was 22.1 months (6.6-not reached) and the median progression-free survival (PFS) was 7.4 months (5.5-30). OS/PFS were 80% (66-99)/78% (64-87) at 1-year, and 59% (44-71)/54% (40-67) at 2-years, respectively. Comprehensive RT to all sites of disease correlated with improved PFS and OS, p ≤ 0.04. Additionally, ECOG ≥2 and Stage III/IV disease predicted poor OS (p ≤ 0.02). Disease bulk, IPI ≥3, and non-GCB histology were poor predictors for disease-specific survival (DSS), p<0.05. The latter two, as well as bRT dose of ≤30 Gy predicted worse PFS (p<0.05). Among patients with advanced stage disease, comprehensive bRT to all sites of disease (n=10) was not associated with improved OS and PFS compared to focal bRT (n=23), p>0.17. No difference was seen in bridging RT vs. chemoRT. Twenty-six patients developed relapse (50.9%), of which 46% was in-field. Risk of in-field relapse correlated with bulky disease (OR=7, 95% CI: 1.2-41, p=0.03) and lack of response at 30 day post-CAR-T evaluation (OR=16.8, 95% CI: 1.6-176, p=0.02), but not with bRT dose (p=0.27).

Conclusion: bRT and CART is a good treatment strategy for select patients with aggressive B cell lymphoma. Comprehensive bRT including all sites of disease is associated with improved outcomes.

A heterozygous mutation in the PTPN2 gene has recently been described in several patients exhibiting symptoms of immune dysregulation. The gene encodes a ubiquitous non-receptor T-cell protein tyrosine phosphatase that exerts a negative feedback on the JAK-STAT pathway. Limited clinical data are available advocating the use of JAK inhibitors as an effective treatment for autoimmune complications of PTPN2 deficiency. However, the mechanism of pathogenesis for these complications suggests this possibility. We report on a 32-year-old male patient with interstitial lung disease, cytopenia, and lymphadenopathy accompanied by de-novo deletion in PTPN2. The patient has been receiving systemic steroid treatment for decades, which has resulted in hormone dependence as well as therapy-related adverse side effects. After the diagnosis of PTPN2 deficiency, treatment with the JAK inhibitor ruxolitinib was initiated at a dose of 15 mg per day, which was escalated to 30 mg daily after 1 month. The steroid treatment was discontinued within 3 months. At the 9- and 16-month checkpoint, after 6 and 13 months correspondingly of monotherapy with ruxolitinib at a dosage of 30 mg per day, the patient had stable blood counts, lymphadenopathy decreased, and the lung interstitial disease improved. Thus, according to our experience, JAK inhibitors are able to alleviate the PTPN2 deficiency symptoms, including hematological changes and interstitial lung damage.

Objective: Establishing biomarkers to predict multiple sclerosis (MS) disability accrual has been challenging using a single biomarker approach, likely due to the complex interplay of neuroinflammation and neurodegeneration. Here, we aimed to investigate the prognostic value of single and multimodal biomarker combinations to predict four-year disability progression in patients with MS.

Methods: In total, 111 MS patients were followed up for four years to track disability accumulation based on the Expanded Disability Status Scale (EDSS). Three clinically relevant modalities (MRI, OCT and blood serum) served as sources of potential predictors for disease worsening. Two key measures from each modality were determined and related to subsequent disability progression: lesion volume (LV), gray matter volume (GMV), retinal nerve fiber layer, ganglion cell-inner plexiform layer, serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein. First, receiver operator characteristic (ROC) analyses were performed to identify the discriminative power of individual biomarkers and their combinations. Second, we applied structural equation modeling (SEM) to the single biomarkers in order to determine their causal inter-relationships.

Results: Baseline GMV on its own allowed identification of subsequent EDSS progression based on ROC analysis. All other individual baseline biomarkers were unable to discriminate between progressive and non-progressive patients on their own. When comparing all possible biomarker combinations, the tripartite combination of MRI, OCT and blood biomarkers achieved the highest discriminative accuracy. Finally, predictive causal modeling identified that LV mediates significant parts of the effect of GMV and sNfL on disability progression.

Conclusion: Multimodal biomarkers, i.e. different major surrogates for pathology derived from MRI, OCT and blood, inform about different parts of the disease pathology leading to clinical progression.

Background: Adaptive human natural killer (NK) cells are an NK cell subpopulation arising upon cytomegalovirus (CMV) infection. They are characterized by CD94/NKG2C expression, a mature CD57⁺KIR⁺NKG2A^- phenotype, a prolonged lifespan, and remarkable antitumor functions. In light of these features, adaptive NK cells represent suitable candidate to design next-generation therapies, based on their enhanced effector function which could be further boosted by Chimeric Antigen Receptors-engineering, or the combination with cell engagers. For therapeutic approaches, however, it is key to generate large numbers of functional cells.

Purpose: We developed a method to efficiently expand adaptive NK cells from NK-enriched cell preparations derived from the peripheral blood of selected CMV-seropositive healthy donors. The method is based on the use of an anti-CD94 monoclonal antibody (mAb) combined with IL-2 or IL-15.

Results: By setting this method we were able to expand high numbers of NK cells showing the typical adaptive phenotype, CD94/NKG2C⁺ CD94/NKG2A^- CD57⁺, and expressing a single self-inhibitory KIR. Expanded cells maintained the CMV-induced molecular signature, exhibited high ADCC capabilities and degranulation against a HLA-E⁺ target. Importantly, mAb-expanded adaptive NK cells did not upregulate PD-1 or other regulatory immune checkpoints that could dampen their function.

Conclusions: By this study we provide hints to improve previous expansion methods, by eliminating the use of genetically modified cells as stimulators, and obtaining effectors not expressing unwanted inhibitory receptors. This new protocol for expanding functional adaptive NK cells is safe, cost-effective and easily implementable in a GMP context, suitable for innovative immunotherapeutic purposes.

Background: Primary central nervous system germ cell tumors (CNS GCTs) are rare intracranial malignancies, and their tumor microenvironment plays a crucial role in tumor initiation and progression. However, the specific characteristics of the immune microenvironment and their clinical significance remain poorly understood.

Methods: This study included 93 paraffin-embedded tissue samples from 90 patients diagnosed with CNS GCTs. Immunohistochemistry and immunofluorescence staining were used to assess the infiltration patterns of T cell subsets (CD3+, CD4+, CD8+, Foxp3+) and the expression levels of immune checkpoints (CTLA-4, PD-1, PD-L1). Additionally, the study explored the relationship between these immune features and the patient's clinical characteristics and prognosis.

Results: The study revealed that germinomas exhibited significantly higher infiltration of CD4+ and Foxp3+ T cells compared to non-germinomatous GCTs (NGGCTs). Additionally, CTLA-4 expression was detected in 58.06% of cases, while PD-1 and PD-L1 were expressed in over 90%, with higher CTLA-4 levels in germinomas and elevated PD-L1 levels in NGGCTs. T cell infiltration was positively correlated with immune checkpoint expression, particularly in germinomas. The results also highlighted the strong immunosuppressive nature of the CNS GCTs' tumor microenvironment. Furthermore, T cell infiltration and immune checkpoint expression were closely associated with clinical characteristics and prognosis. Notably, PD-1 expression was identified as an independent prognostic factor for progression-free survival (PFS) and recurrence-free survival (RFS).

Conclusion: Our study highlighted the distinct characteristics of T cell infiltration and the significant expression of immune checkpoints in CNS GCTs, revealing the highly heterogeneous and immunosuppressive nature of the tumor microenvironment. PD-1 expression was identified as an independent prognostic predictor, offering a foundation for enhancing risk stratification in CNS GCT patients. These findings also support the potential for future clinical applications of immune checkpoint inhibitors, such as PD-1 monoclonal antibodies.

Background: Strong correlations have been shown between systemic oxidative stress (SOS) and the occurrence, metastasis, and prognosis of many types of cancers. It is yet unknown how SOS levels relate to the prognosis of esophageal squamous cell carcinoma (ESCC). The current research aims to explore the prognostic role of systemic oxidative stress index (SOSI) on ESCC receiving neoadjuvant immunochemotherapy (nICT).

Methods: Retrospective recruitment was used to identify 224 nICT-treated ESCC patients. In order to determine the integrative score of SOSI, logistic regression analyses were utilized to screen independent risk variables, with disease-free survival (DFS) serving as the dependent variable. Given the non-linear relationship between SOSI and DFS, the best threshold was determined using a restricted cubic spline (RCS) model. Independent variable determination was executed using a cox regression analysis. For prognostic prediction, a risk categorization method based on recursive partitioning analysis (RPA) was also created.

Results: Four SOS-related indicators, including albumin, creatinine, blood urea nitrogen, and direct bilirubin, were used to establish the SOSI. The ideal threshold of SOSI, shown by the non-linear relationship between DFS and SOSI (P<0.001), was used to compare between two groups. As a potential prognostic factor for those nICT-treated ESCC patients, SOSI showed a strong correlation with both DFS and overall survival (OS). Patients with low SOSI had better DFS (55.1% vs. 85.5%, P<0.001) and OS (72.6% vs. 79.1%, P=0.013). Then, a new staging that included TNM and SOSI based on RPA algorithms was produced. In terms of prognostication, the RPA model performed significantly better than TNM classification.

Conclusion: SOSI is a simple and useful score based on available SOS-related indices. In ESCC receiving nICT, low SOSI is found to be an important factor of better prognosis.

Goblet cell hypersecretion is a hallmark of airway inflammation and is driven by complex neuroimmune regulation involving submucosal glands and goblet cells. Although studies have focused on mast cell degranulation as a critical driver of nasal secretion, the role of goblet cells in this process is relatively under-researched. In allergic airway inflammation, goblet cells exhibit metaplasia and hypersecretion. However, allergen exposure does not directly trigger goblet cell degranulation, raising questions regarding the underlying mechanisms of these reactions. The activation of enteric neurons promotes goblet cell degranulation by stimulating the calcitonin gene-related peptide (CGRP)-receptor active modification protein-1 (RAMP1) axis. Meanwhile, airway goblet cells express various neuropeptide receptors, and their activation by neuropeptides such as substance P and CGRP induces mucus secretion, exacerbating allergic rhinitis-associated hypersecretion. Thus, although previously less recognised, the neuron-goblet cell signalling axis plays a critical role in allergic rhinitis mucus secretion. This review highlights current research on the neuroimmune mechanisms underlying goblet cell metaplasia and degranulation, focusing on allergic rhinitis, so as to guide clinical treatment strategies.

One of the major consequences of schistosomiasis is its impact on brain function, and despite its severity, the underlying mechanism(s) remain inadequately understood, highlighting a knowledge gap in the disease. The symptoms can vary from headaches to profound cognitive impairment. Besides, the potential influence of physical exercise in mitigating cognitive deficits has received little attention. In our study, we utilized a murine model of Schistosoma mansoni infection to investigate the cognitive impact of schistosomiasis. Our aims were multifaceted: to pinpoint the specific cognitive domains affected during the infection in adult mice, to unravel the complex interplay between glial and immune cells within the central nervous system (CNS), and crucially, to explore the potential therapeutic role of regular physical exercise in counteracting the deleterious effects of schistosomiasis on the CNS. Our findings unveiled that while acute infection did not disrupt simple and complex learning or spatial reference memory, it did induce significant deficits in recall memory-a critical aspect of cognitive function. Furthermore, our investigation unearthed profound alterations in the immune and glial cell populations within the CNS. Notably, we observed marked changes in CD4⁺ T cells and eosinophils in the meninges, as well as alterations in glial cell dynamics within the hippocampus and other brain regions. These alterations were characterized by heightened microglial activation, diminished astrocyte reactivity and a shift towards a proinflammatory milieu within the CNS. We also provided insights into the transformative potential of regular moderate physical exercise in partially alleviating cognitive and neuroinflammatory consequences of schistosomiasis. Remarkably, exercise decreased glial cell production of TNFα, suggesting a shift towards a less pro-inflammatory environment. Collectively, our study provided compelling evidence of the intricate interplay between schistosomiasis infection and cognitive function, underscoring the critical need for further exploration in this area. Furthermore, our findings demonstrated the positive effects of physical activities on mitigating the cognitive burden of schistosomiasis, offering new hope for patients afflicted by this debilitating disease.