ImmunoTargets and Therapy最新文献

Background: COVID-19 is a serious viral infection, which is often associated with a lethal outcome. Therefore, understanding mechanisms, which affect the immune response during SARS-CoV2 infection, are important.

Methods: To address this, we determined the number of T cells in peripheral blood derived from intensive care COVID-19 patients. Based on our previous studies, evaluating PPARγ-dependent T cell apoptosis in sepsis patients, we monitored PPARγ expression. We performed a next generation sequencing approach to identify putative PPARγ-target genes in Jurkat T cells and used a PPARγ transactivation assay in HEK293T cells. Finally, we translated these data to primary T cells derived from healthy donors.

Results: A significantly reduced count of total CD3⁺ T lymphocytes and the CD4⁺ and CD8⁺ subpopulations was observed. Also, the numbers of anti-inflammatory, resolutive T_h2 cells and FoxP3-positive regulatory T cells (T_reg) were decreased. We observed an augmented PPARγ expression in CD4⁺ T cells of intensive care COVID-19 patients. Adapted from a next generation sequencing approach in Jurkat T cells, we found the chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2) as one gene regulated by PPARγ in T cells. This T_h2 marker is a receptor for prostaglandin D and its metabolic degradation product 15-deoxy-∆12,14-prostaglandin J₂ (15d-PGJ₂), an established endogenous PPARγ agonist. In line, we observed an increased PPARγ transactivation in response to 15d-PGJ₂ treatment in HEK293T cells overexpressing CRTH2. Translating these data to primary T cells, we found that T_h2 differentiation was associated with an increased expression of CRTH2. Interestingly, these CRTH2⁺ T cells were prone to apoptosis.

Conclusion: These mechanistic data suggest an involvement of PPARγ in T_h2 differentiation and T cell depletion in COVID-19 patients.

Objective: To investigate the causal relationship between 91 circulating inflammatory proteins and Various asthma phenotypes by means of Mendelian randomization.

Methods: Genome-wide association Studies (GWAS) of 91 inflammatory proteins were pooled from the Olink Target platform with 14,824 participants. Various asthma phenotypes were derived from the FinnGen Biobank. Inverse variance weighting (IVW) was used as the main method for MR Analysis, supplemented by Mr-Egger, Weighted median, Simple mode, and Weighted mode. The MR-Egger intercept term test and Cochran's Q test were used to test the polymorphism and heterogeneity of IVs, and visual analysis was carried out to draw scatter plots, funnel plots, and leave-out-one plots. The FDR correction was performed due to the possibility of a type 1 error.

Results: Genetically predicted IVW results revealed a total of 30 data sets suggesting a potential causal relationship between circulating inflammatory proteins and asthma phenotypes. Among them, 2 results were still strongly positive after FDR correction. The level of CST5 (OR=1.184; 95% CI: 1.075-1.305; P=0.0001; P-FDR=0.028) is associated with an increased risk of non-allergic asthma. LIF-R (OR=0.723; 95% CI: 0.620-0.842; P=0.000; P-FDR=0.003) is associated with a reduced risk of asthma in children. There was no pleiotropy or heterogeneity in the remaining 16 results that suggested a potential causal relationship.

Conclusion: Increased CST5 levels are associated with an increased risk of non-allergic asthma. LIF-R is associated with a reduced risk of asthma in children.

Background: Endometriosis is a complex gynecological condition in which endometrial fragments are implanted outside the uterus, causing pain and infertility. Although immune mediators play a vital role in endometriosis, their exact etiology remains elusive. Using Mendelian randomization (MR), this study aimed to assess the causal relationship between inflammatory proteins and endometriosis.

Methods: Genetic variants associated with inflammatory proteins were filtered from a genome-wide protein quantitative trait locus study under stringent thresholds. These variants were used as instrumental variables (IVs) to evaluate the causal effects of these inflammatory proteins on endometriosis. A two-sample MR analysis was performed with endometriosis from the UK Biobank as the outcome, and a sensitivity analysis was performed to mitigate potential confounding factors. Analyses were replicated in an independent endometriosis cohort from the FinnGen, followed by a meta-analysis of MR results from both cohorts. Finally, we assessed the causality between inflammatory proteins and the endometriosis subtypes.

Results: Independent MR analysis revealed that the genetically higher levels of CXCL5 were linked to a lower chance of having endometriosis. The causal link remained significant in the meta-analysis. Furthermore, the causality of CXCL5 expression has been identified in ovarian and pelvic peritoneal endometriosis.

Conclusion: Our MR analysis indicated that CXCL5 was associated with a decreased risk of endometriosis, suggesting that CXCL5 might have a protective effect against endometriosis. This enhances our understanding of the involvement of chemokines in endometriosis pathology and provides insights for future studies to explore the detailed mechanisms underlying CXCL5 in endometriosis.

Background: Immune checkpoint inhibitors (ICIs) has prolonged survival in patients with extensive-stage small cell lung cancer (ES-SCLC) as first-line treatment. However, whether ICI rechallenge could bring survival benefit to patients with ES-SCLC following its failure as first-line treatment remains unknown. Therefore, we aim to address the issue and identify the cohort of patients that may derive such benefit.

Methods: Patients with ES-SCLC from both the IMpower133 study and Shandong Cancer Hospital and Institute (shanzhong cohort) who failed first-line ICI were included. Kaplan Meier analysis was performed to compare overall survival (OS). Both univariate and multivariate Cox regression analyses were conducted to identify factors affecting survival. Tumor immune cell infiltration was evaluated by the CIBERSORT algorithm and detected by multiplex immunofluorescence (mIF).

Results: A total of 125 ES-SCLC patients undergoing atezolizumab and 161 patients undergoing ICI as first-line treatment were recruited from IMpower133 and shanzhong cohort. Those receiving ICI rechallenge had a longer OS than those without in IMpower133 (P = 0.08) and shanzhong cohort (P = 0.013). In IMpower133 cohort, subgroup analyses found that patients with <4 metastatic sites derived more survival benefit from atezolizumab (P = 0.008). For patients with ES-SCLC harboring <4 metastatic sites, there was significant OS difference between atezolizumab versus non-atezolizumab as retreatment (P = 0.036). Moreover, for ES-SCLC patients with <4 metastatic sites, atezolizumab improved survival compared with non-atezolizumab (hazard ratio [HR]: 0.457; 95% CI: 0.256-0.817; P = 0.008). These findings were confirmed in shanzhong cohort. Those harboring <4 metastatic sites had fewer M2 macrophage and more CD4 naïve T cells infiltration, which was further confirmed by mIF of ES-SCLC samples from shanzhong cohort.

Conclusion: Our study provides rationale for ICI rechallenge among ES-SCLC patients with <4 metastatic sites, suggesting beneficial outcome by reshaping TME.

Objection: To report the efficacy and safety of triple combination therapy with bevacizumab plus anti-PD-1 (BP1) or anti-PD-L1 inhibitors (BPL) combined with hepatic arterial infusion chemotherapy (HAIC) as a first-line treatment for initially unresectable hepatocellular carcinoma (uHCC).

Methods: In this retrospective study, patients with initially uHCC received either BP1-HAIC or BPL-HAIC as first-line treatment. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), objective response rate (ORR) and disease control rate (DCR).

Results: Between January 2020 and December 2022, a total of 136 patients with initially uHCC received triple combination therapy, with 76 in the BP1-HAIC group and 60 in the BPL-HAIC group. The median PFS for the entire cohort was 11.1 months (95% CI, 8.0-13.7 months), and the median OS was 22.4 months (95% CI, 21.3- not reached). Comparative analysis revealed no significant differences in PFS (HR, 0.91, P = 0.69) or OS (HR, 0.71, P = 0.31) between the BP1-HAIC and BPL-HAIC groups. The ORR was 46.3% per RECIST v1.1 and 66.9% per mRECIST, with a DCR of 83.1% under both criteria. Common adverse events (AEs) included hypoalbuminemia and elevated aspartate/alanine aminotransferase, with 5.1% (7/136) experienced upper gastrointestinal bleeding. Multivariate Cox analysis identified tumor number and BCLC stage as independent prognostic factors for OS, and tumor number for PFS.

Conclusion: Triple combination therapy demonstrated significant therapeutic efficacy and tumor response in initially uHCC. No notable differences in outcomes were observed between the BP1-HAIC and BPL-HAIC groups. AEs were manageable in clinical practice.

Purpose: The response of patients with biliary tract carcinoma (BTC) to immunotherapy varies widely, and there is an urgent need for biological indicators. The predictive value of inflammation based score (IBS) for the efficacy of immunotherapy in patients with BTC remains unclear, as the evidence is inconsistent. This study aimed to comprehensively examine the predictive value of IBS in peripheral blood on the survival of BTC patients receiving immunotherapy.

Patients and methods: We retrospectively assessed 118 patients with advanced BTC who received anti-PD-1 therapy in the first or second line in two medical centers. The Kaplan-Meier, time-dependent ROC, and Harrell's concordance index (C-index) were applied to analyze the predictive value of 13 reported peripheral blood IBS.

Results: All 13 IBS were identified as significant prognostic factors for OS in univariate analysis. Pan-immune-inflammation value (PIV) (p=0.005), PILE (composed of PIV, lactate dehydrogenase and Eastern Cooperative Oncology Group performance status) (p=0.033), neutrophil-to-lymphocyte ratio (NLR) (p=0.003), platelet-to-lymphocyte ratio (PLR) (p<0.001), lymphocyte-to-monocyte ratio (LMR) (p=0.006), systemic immune inflammation index (SII) (p=0.039), CRP-to-albumin ratio (CAR) (p=0.025), and Albumin-NLR (p=0.008) were identified as independent prognostic factors for OS in multivariate analysis. PIV and PILE scores were superior to other scores, according to time-dependent ROC curves, and their superiority became more pronounced after the 12-month time point. C-index analysis showed PIV (C-index 0.62, 95% CI: 0.55, 0.68) and PILE (C-index 0.62, 95% CI: 0.55, 0.70), both superior to other IBS.

Conclusion: PIV and PILE scores are independent predictors of OS in patients with BTC after immunotherapy and are superior to other IBS. PIV and PILE may be able to help screen out patients with advanced BTC who are less likely to benefit from anti-PD-1 monotherapy. Due to the retrospective nature of this analysis, the predictive value of PIV and PILE require validation in further prospective studies.

Lack of response to immunotherapies poses a significant challenge in treating immune-mediated disorders and cancers. While the mechanisms associated with poor responsiveness are not well defined and change between and among subjects, the current methods for overcoming the loss of response are insufficient. The Constrained Disorder Principle (CDP) explains biological systems based on their inherent variability, bounded by dynamic boundaries that change in response to internal and external perturbations. Inter and intra-subject variability characterize the immune system, making it difficult to provide a single therapeutic regimen to all patients and even the same patients over time. The dynamicity of the immune variability is also a significant challenge for personalizing immunotherapies. The CDP-based second-generation artificial intelligence system is an outcome-based dynamic platform that incorporates personalized variability signatures into the therapeutic regimen and may provide methods for improving the response and overcoming the loss of response to treatments. The signatures of immune variability may also offer a method for identifying new biomarkers for early diagnosis, monitoring immune-related disorders, and evaluating the response to treatments.

Background: Enhancing NK cells' antitumor activity requires sustained cytokine signaling. Interleukin-15 (IL-15) is a potent immunostimulatory cytokine used to armor CAR-NK and CAR-T cell immunotherapies. However, strategies to increase IL-15 expression and antitumor effect may trigger systemic toxicity with the potential to promote oncogenesis and autoimmune diseases.

Methods: To overcome these limitations, we developed a new platform (IL15RB) whereby IL-15 with IL-2 signal peptide is tethered to its receptor, IL2Rβ.

Results: NK92-expressing IL15RB (NK92^IL15RB) cells expand indefinitely without exogenous cytokines and have significantly higher anticancer activity than NK-92 stimulated by IL-15, IL-2, or expressing tethered IL-2. NK92^IL5RB showed resistance to irradiation and IL-4. However, TGFβ1 substantially reduced NK92^IL5RB killing, suggesting the need to inhibit TGFβ1 in IL-15-mediated immunotherapies. IL15RB induced strong STAT3 but weaker STAT5 and STAT1 activation compared to IL-2. Chronic exposure of NK92^IL15RB cells to cancer cells reduced STAT3 and STAT1 activation irreversibly, suggesting a role in exhaustion. Combination with CAR-CD19 enhanced NK92^IL15RB antitumor activity against leukemia and increased its STAT5 activation. NK92^IL15RB anti-tumors activity was further enhanced by combination with anti-PD1.

Conclusion: Our data suggest that the tethering of IL-15 to its receptor IL2Rβ empowers NK cell cytolytic activity. Additionally, the tethering of IL-15 will prevent any systemic risk of toxicity.

Background: Cyclin-dependent kinase (CDK) 4/6 inhibitors have revolutionized the treatment landscape of hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2 -) metastatic breast cancer (MBC). Here, we present the real-world clinical outcomes and toxicity data of patients treated at a single cancer center.

Methods: A retrospective analysis was conducted on patients with HR+/HER2- MBC treated with ribociclib plus endocrine therapy (ET). Outcomes measured included progression-free survival (PFS), overall survival (OS), and adverse events.

Results: A total of 356 patients (median age 52, range 27-91 years) were enrolled, all with metastatic disease; 204 (57.5%) had de novo metastasis, and 183 (51.4%) had visceral metastasis. Ribociclib was combined with aromatase inhibitors in 321 patients (90.2%) and with fulvestrant in 35 patients (9.8%). Dose reduction was needed in 101 patients (28.4%), primarily due to neutropenia (21.3%) and abnormal liver enzymes (5.9%). After a median follow-up of 36.3 months, median PFS was 27.3 months (95% CI: 21.3-31.7). PFS was significantly better in patients receiving ribociclib as first-line therapy (32.1 months, 95% CI: 27.7-42.1, p < 0.0001) and those with non-visceral metastasis (38.6 months, 95% CI: 29.8-NR, p < 0.0001). Similarly, OS was significantly better in first-line treatment (48.6 months, 95% CI: 39.1-NR) and non-visceral metastasis cases (NR, 95% CI: 40.6-NR, p < 0.0001). No significant differences in 3-year PFS and OS were found between patients with and without dose reductions.

Conclusion: In real-world settings, and away from the stringency of controlled clinical trials, endocrine therapy in combination with ribociclib in patients with HR-positive/HER2-negative MBC is an effective and well-tolerated therapy with a manageable toxicity profile and a low drug discontinuation rate. Dose reduction due to toxicity did not worsen the outcome.

Background: Respiratory viral infections are a leading cause of severe diseases and mortality; therefore, novel treatments effective for their prevention are highly requested. Here, we identified a broad-spectrum antiviral activity of a natural exopolysaccharide, EPS T14, purified from a marine thermotolerant strain of Bacillus licheniformis strain T14.

Methods: The effects on human normal nasal epithelial cells (HNEpCs) following treatment with EPS T14 was evaluated at different time points and with increasing concentration of compound. To assess the antiviral properties, viability of HNEpCs treated with EPS T14 was analysed following infection with different respiratory viruses.

Results: Neither toxicity nor pro-inflammatory properties were observed in vitro on HNEpCs treated with EPS T14 up to high concentrations, thus ensuring its safety. Cell culture-based assays revealed that treatment of HNEpCs with EPS T14 (used at 400ug/mL) results in efficient prevention of cell infection by different respiratory viruses through physically hindering the entry of the viruses via cell surface receptors. Interestingly, in addition to this prophylactic antiviral activity, EPS T14 also shows a long-lasting efficacy by inhibiting viral spread in the cell culture. Finally, combination of EPS T14 with a hypertonic saline solution shows a synergistic antiviral activity.

Conclusion: EPS T14 can exert both prophylactic and therapeutic antiviral activity by blocking viral attachment to cellular receptors and could therefore represent a promising antiviral agent for preventing infections by different respiratory viruses.