Frontiers in Immunology最新文献

Introduction: CXCL8, belonging to inflammatory chemokines, is expressed by various cell types and plays a key role in leukocyte trafficking during infections, inflammatory processes, tissue injury and tumor progression. Chemokines interact not only with G-protein coupled receptors but also with glycosaminoglycans (GAGs), which are polyanionic linear polysaccharides. Chemokine-GAG interactions are critical for creating localized concentration gradients, protecting chemokines from degradation, and maintaining their efficacy in vivo.

Methods: We have previously engineered a CXCL8-based dominant-negative decoy ("PA401") with strongly increased GAG binding affinity combined with complete GPCR knockout, which was originally developed for the treatment of COPD. Here we have optimized our engineering protocol by minimizing CXCL8 mutations while conserving its in vitro dominant-negative activities. This novel CXCL8-based decoy (mtCXCL8) was further fused to human serum albumin (HSA) to overcome the typically very short serum half-life of chemokine-based biologics. We are therefore able to present here an entirely novel CXCL8-based biologic (hsa/mtCXCL8) which reflects our threefold modification strategy - increasing GAG-binding affinity by minimal mutagenesis, GPCR knockout, and fusion to HSA - thus representing a comprehensive and novel approach towards addressing chronic CXCL8-driven diseases.

Results: In the current study, we have investigated the immunomodulatory potential of our new decoy in a 3-D cellular tumor model ("BioMAP") which relates the biomarker interaction profile of immune and tumor cells to a data-base mirrored biomarker read-out. The obtained BioMAP results suggest an impact of hsa/mtCXCL8 on the immune compartment of the VascHT29 cell model by modulating cytokine levels and inhibiting immune cell activation markers. When combined with Keytruda (Pembrolizumab), a PD-1 inhibitor, it enhances some of its known activities, indicating potential synergistic effects, but further investigation is needed due to the observed increase in soluble IL-6 and limitations in dose selection for future in vivo studies.

Discussion: By prolonging the presence of engineered chemokine mutants in the bloodstream and optimizing their stability, these strategies aim to enhance the therapeutic efficacy of CXCL8-based interventions, offering promising avenues for the treatment of several CXCL8-mediated pathologies, including cancer.

In line with encountering the world with the emergence of vaccine-resistance variants of SARS-CoV-2, 15,669,529 samples that received COVID-19 vaccines until April 2023 were investigated as two doses in the first phase and booster vaccinations in the second phase. The analysis shows that D614G and P681 mutations occurred in both phases. The E484 and Y655 mutations significantly emerged during the second phase. The 762-889 and 254-381 regions are revealed as conserved parts and could be considered in vaccine design. The Kruskal-Wallis test revealed a significant reduction in single mutations between populations with 20%-50% and those with 70%-100% vaccination coverage (p=0.017). The Mann-Whitney U test proposes a link between vaccination and suppression of viral mutation rates. Dynamic modeling suggests that key mutations have facilitated the virus' evolution and immune escape. The study's findings are crucial for understanding virus genome mutations, especially E614 and P681 in Delta and E484 and H655 in Omicron. This highlights the need to adjust strategies and strengthen global efforts in combating the pandemic.

[This corrects the article DOI: 10.3389/fimmu.2021.789317.].

Objective: Camrelizumab, a programmed death-1 inhibitor, is effective and safe for treating patients with advanced lung cancer according to previous phase 3 trials. However, relevant real-world clinical evidence is required. This study intended to explore the efficacy and safety of camrelizumab-based therapies in patients with advanced lung cancer.

Methods: Patients with advanced lung cancer who received camrelizumab-based therapies as first-line or above treatment were consecutively enrolled in this study. The median follow-up duration was 5 months.

Results: A total of 298 subjects were enrolled. Objective response rate (ORR) and disease control rate (DCR) were 27.2% and 82.2%. Multivariable logistic regression analysis showed that previous pulmonary surgery [odds ratio (OR)=0.440, P=0.024], previous radiotherapy (OR=0.410, P=0.010), and Eastern Cooperative Oncology Group Performance Status (ECOG PS) score (>1 vs. 0~1) (OR=0.414, P=0.046) were independently and negatively associated with ORR. The median progression-free survival (PFS) [95% confidence interval] was 10.0 (7.8-12.2) months. Median overall survival (OS) was not reached. Multivariable Cox regression analysis suggested that brain metastasis [hazard ratio (HR)=1.548, P=0.036] and liver metastasis (HR=1.733, P=0.035) were independently associated with shorter PFS. Previous chemotherapy (HR=2.376, P=0.022), brain metastasis (HR=2.688, P=0.006), and liver metastasis (HR=2.583, P=0.039) were independently associated with shorter OS. Most adverse events were grade I or II. Grade III and IV adverse events rarely occurred. The occurrence of adverse events was associated with a higher DCR (P=0.003).

Conclusions: Camrelizumab-based therapies may serve as potential treatments for patients with advanced lung cancer. However, further studies with an extended follow-up duration are warranted.

The chondrocyte sheet is a sheet-like cell structure obtained by separating in vitro expanded and fused autologous chondrocytes from the bottom of the culture dish by physical means. The cell sheet contains autologous chondrocytes, extracellular matrix secreted by chondrocytes, and connective structures established between cells and matrix, and between cells and cells. In cartilage tissue engineering, chondrocyte sheets technology has great potential for the treatment of cartilage defects. Chondrocyte sheets have a low immunogenicity because they avoid the immune reaction caused by scaffolding materials. However, chondrocyte sheets can still cause severe local tissue swelling in the short term after implantation, resulting in a poor patient experience. In individual cases, an inflammatory reaction may even occur, leading to resorption of the chondrocyte sheet. This may be immunogenetically related to chondrocyte membrane surface-associated antigens, components of the extracellular matrix secreted by chondrocytes, and various bioactive components in the culture medium used during in vitro chondrocyte culture. Therefore, in order to investigate the causes of local tissue swelling and immune-inflammatory reactions induced by the implantation of chondrocyte sheets, this article reviews the immunogenicity of chondrocyte-associated antigens, components of the extracellular matrix of cartilage, and the active components of the cell culture medium.

Introduction: Cancer remains the leading cause of death worldwide, with increasing incidence rates. Natural compounds have gained attention as potential therapeutic agents due to their bioactive properties. Anthocyanins, particularly delphinidin-3-sambubioside (Dp-3-sam) and cyanidin-3-sambubioside (Cn-3-sam), are flavonoids with antioxidant and potential antitumor properties. This study investigates the antitumor effects of anthocyanins extracted from Hibiscus sabdariffa L. (H. sabdariffa), administered intratumorally, and their potential as adjuvants to chemotherapy.

Methods: Anthocyanins were extracted from H. sabdariffa and characterized using high-performance liquid chromatography (HPLC). The total phenolic content was determined using the Folin-Ciocalteu method. Antioxidant activity was assessed through DPPH, ABTS, and FRAP assays. The antiproliferative effects of Dp-3-sam and Cn-3-sam were evaluated in vitro using MCA-205 fibrosarcoma and CT26 colon carcinoma cell lines. In vivo studies were conducted on mouse tumor models to assess tumor growth inhibition following intratumoral administration of anthocyanins alone or in combination with doxorubicin. The impact on angiogenesis, immune cell recruitment, and long-term immune memory was also analyzed.

Results: HPLC analysis confirmed the presence of Dp-3-sam and Cn-3-sam in the H. sabdariffa extract. The anthocyanins exhibited significant antioxidant activity in all assays. In vitro studies demonstrated dose-dependent inhibition of cancer cell proliferation. In vivo, intratumoral administration of anthocyanins led to a significant reduction in tumor growth. The combination of anthocyanins with doxorubicin further enhanced tumor suppression. Mechanistically, Dp-3-sam and Cn-3-sam reduced angiogenesis and promoted immune cell recruitment but did not elicit an effective antitumor immune response alone. However, co-administration with doxorubicin reversed this limitation, leading to increased immune activation and resistance to tumor rechallenge, suggesting the induction of long-term immune memory.

Discussion: These findings highlight the potential of H. sabdariffa-derived anthocyanins as adjuvants in cancer therapy. When administered intratumorally, they enhance chemotherapy efficacy and immunogenicity. However, further studies are needed to optimize dosing strategies, evaluate long-term safety, and assess clinical applicability.

Allogeneic natural killer (NK) cell therapy has demonstrated significant potential in cancer immunotherapy by harnessing NK cells to target malignancies. CD138-targeting chimeric antigen receptor (CAR)-engineered NK cells offer a promising therapeutic option for multiple myeloma (MM). However, sustaining CAR expression on CAR-NK cells during ex vivo expansion poses a challenge to developing effective immunotherapies. In this study, primary NK cells were isolated, cryopreserved, and modified to express anti-CD138 CARs through retroviral transduction. Histone deacetylase inhibitors (HDACi), particularly entinostat (ENT), were applied to enhance CAR expression stability in CAR-NK cells. Our findings indicate that ENT treatment significantly improves and maintains CAR expression, thereby enhancing the cytotoxic activity of CAR-NK cells against CD138-positive multiple myeloma cells. ENT-treated CAR-NK cells exhibited prolonged persistence and more significant tumor reduction in an MM tumor-bearing mouse model, highlighting the therapeutic potential of HDACi-treated CAR-NK cells. This study provides the first evidence that HDAC inhibitors can sustain CAR expression in CAR-NK cells in a promoter-dependent manner, potentially enhancing anti-tumor efficacy in multiple myeloma and underscoring the possible need for further clinical evaluation.

Ulcerative colitis (UC) is an incurable autoimmune disease. Patients with UC endure the burden of recurrent flare-ups and face a substantial economic burden due to long-term medication. The complex etiology and unclear pathogenesis pose a significant challenge to the development of effective and curative treatments. Recent research indicates that local memory at the site of inflammatory intestinal mucosa in UC is closely associated with the persistent presence of tissue-resident memory T (TRM) cells. TRM cells, a subset of memory T cells, exhibit long-lived, low-migration characteristics. These cells reside in tissues, where they provide immediate immune protection while also contributing to chronic, localized inflammation. The presence of TRM cells in the inflamed intestinal mucosa of UC patients is a crucial factor in the recurrence of the disease. However, the process involved in the formation and differentiation of TRM cells within the intestinal mucosa remains poorly understood. Various surface markers, transcriptional networks, and signaling pathways regulate the formation and maintenance of TRM cells in the intestine. To further understand the role of TRM cells in UC pathogenesis, we have summarized the latest findings to pave the way for the development of future targeted therapies.

Aims: Immune-related adverse events (irAEs) pose a significant challenge to the clinical use of immune checkpoint inhibitors (ICIs) in cancer immunotherapy. This study aims to determine whether comorbid conditions such as type 2 diabetes (T2DM), hypertension, and hyperlipidemia affect the risk of irAEs in cancer patients receiving ICIs treatments.

Materials and methods: We conducted a retrospective analysis of clinical data from 3,489 cancer patients treated with ICIs (anti-PD-1, anti-PD-L1, and anti-CTLA-4) at West China Hospital of Sichuan University from 2017 to 2022. Logistic regression models were used to evaluate the associations between T2DM, hypertension, and hyperlipidemia with irAEs. Subgroup analyses assessed irAEs in patients with and without these comorbidities across different cancer types. Additionally, we explored the associations between comorbidities and irAEs affecting different organs.

Results: The results showed that comorbid T2DM, hypertension, and hyperlipidemia significantly increased the risk of irAEs in all cancer types (T2DM: OR=1.40, 95% CI: 1.12-1.74, p=0.003; hypertension: OR=1.21, 95% CI: 1.00-1.45, p=0.049; hyperlipidemia: OR=1.62, 95% CI: 1.02-2.53, p=0.038). T2DM primarily increased the risk of irAEs in lung cancer patients (OR = 1.50, 95% CI: 1.12-2.01, FDR-adjusted p = 0.036), and all three comorbidities significantly elevated the risk of cardiac irAEs.

Conclusions: Our study is the first to confirm an association between T2DM, hypertension, and hyperlipidemia and the occurrence of irAEs in cancer patients receiving ICIs therapy. This finding highlights the critical need for clinicians to perform comprehensive evaluations of patients' comorbidities prior to treatment.

Purpose: In this study, we aimed to develop a predictive model for patients receiving chemotherapy and immunotherapy for extensive-stage small cell lung cancer.

Methods: We retrospectively analyzed 112 extensive-stage small cell lung cancer patients treated with first-line immunotherapy and chemotherapy. The relevant clinical data were collected to evaluate the changes during the treatment. The best subset regression, univariate analysis, and LASSO regression with cross-validation were applied for variable selection and model establishment. The nomograms for 1- and 2-year survival probabilities were established, and the calibration curve was utilized to evaluate the correspondence between actual and predicted survival. The model prediction capacity was assessed using decision curve analysis, calibration curves, and receiver operating characteristic curves. Moreover, five-fold cross-validation was conducted for internal validation. According to risk score, the patients were assigned to high- and low-risk groups, and survival curves were generated for each group.

Results: The LASSO regression model was established based on the variables such as age, ECOG, metastatic sites, NLR, and immunotherapy cycles. This predictive model displayed robust performance, evidenced by the Area Under the Curve of 0.887 and concordance index of 0.759. The nomogram effectively predicted 1- and 2-year survival probabilities and demonstrated a high degree of calibration. The decision curve analysis displayed that the model possessed superior predictive capability. The risk stratification for patients with high- and low-risk categories facilitated more individualized survival assessment.

Conclusion: The study successfully developed a prognostic model for extensive-stage small cell lung cancer patients undergoing immunotherapy and chemotherapy, demonstrating the good accuracy and predictability.