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关键词： cytokines   interleukin-6   luminal A   macrophages   non-responder   T cells  

摘要： Drug non-responsiveness is the major reason for the poor prognosis of hormonal receptor-positive breast cancer (ER+/PR+ BCa), particularly the luminal A subtype. However, the underlying mechanism of drug non-responsiveness remains unknown. Flow cytometry and t-SNE analysis followed by ELISA validation of responder and non-responder unveiled lower secretion of IFN-gamma, IL-12, and higher levels of IL-6 and TGF-beta in CD4(+) T cells (P < 0.001), CD8(+) T cells (P < 0.001), FOXP3(+) Tregs (P < 0.001) and CD206(+) TAMs (P < 0.001) in non-responders. Treatment of isolated CD206(+) TAMs with recombinant IL-6 upregulated the expression of ARG-1 (arginase-1) and subsequent increase of TGF-beta(+) Tregs (P < 0.001) and IL-6(+) Tregs (P < 0.001) in luminal A BCa. Our findings showed IL-6 mediated ARG-1(+)CD206(+) TAMs polarization induced FOXP3(+) Tregs infiltration in TME of non-responder in luminal A BCa.

关键词： Hypoxia   MHC I Expression   Antigen Presentation   Autophagy   Immune Response  

摘要： Hypoxia is a common feature of solid tumors that has previously been linked to resistance to radiotherapy and chemotherapy, and more recently to immunotherapy. In particular, hypoxic tumors exclude T cells and inhibit their activity, suggesting that tumor cells acquire a mechanism to evade T-cell recognition and killing. Our analysis of hypoxic tumors indicates that hypoxia downregulates the expression of MHC class I and its bound peptides (i.e., the immunopeptidome). Hypoxia decreases MHC-I expression in an oxygen-dependent manner, via activation of autophagy through the PERK arm of the unfolded protein response. Using an immunopeptidomics-based LC-MS approach, we find a significant reduction of presented antigens under hypoxia. Inhibition of autophagy under hypoxia enhances antigen presentation. In experimental tumors, reducing mitochondrial metabolism through a respiratory complex-I inhibitor increases tumor oxygenation, as well as MHC-I levels and the immunopeptidome. These data explain the molecular basis of tumor immune evasion in hypoxic conditions, and have implications for future therapeutic interventions targeting hypoxia-induced alterations in antigen presentation.

摘要： PURPOSE:This study explored the combination of FAP-IL2v, a novel immune-cytokine, with pembrolizumab in patients with advanced and/or metastatic melanoma. PATIENTS AND METHODS:This open-label, multicenter, phase 1b clinical study (NCT03875079) evaluated the safety, tolerability, pharmacodynamics, pharmacokinetics (PK), and antitumor activity of FAP-IL2v (simlukafusp alfa, RO6874281) in combination with pembrolizumab. Patients with advanced and/or metastatic melanoma were either checkpoint inhibitor (CPI)-naïve or -experienced. Patients received 10 mg FAP-IL2v either continuously once every three weeks (Q3W) or in an induction/maintenance setting consisting of a 3-week induction phase with weekly (QW) dosing followed by continuous Q3W dosing. Pembrolizumab was dosed Q3W at 200 mg. RESULTS:Eighty-three patients were treated, 16 patients in two safety run-in cohorts, and 67 patients in two extension cohorts; 75 (90.4%) patients were CPI-experienced. The PK of FAP-IL2v in combination with pembrolizumab was similar to that after administration as monotherapy. Consistent with the proposed mode-of-action, FAP-IL2v preferentially expanded NK and CD8 T cells. The most common FAP-IL2v-related grade 3/4 AEs were lymphopenia (23%), elevated γ‑glutamyltransferase (8%), elevated alanine aminotransferase (6%), and infusion-related reaction (6%). A response was observed in 5 of 75 (6.7%) CPI-experienced patients (all partial responses) and in 2 of 8 CPI-naïve patients (one complete, one partial response). The median progression-free survival was 3.1 months. CONCLUSIONS:The safety profile of FAP-IL2v in combination with pembrolizumab was manageable and consistent with the known safety profile. However, further exploration of FAP-IL2v and pembrolizumab was precluded in melanoma patients with prior CPI due to the lack of clinical activity.

关键词： Lifestyle   glucose   inflammation   cytokine   gestation  

摘要： It is unclear how exercise-induced stimuli affect and translate into immunometabolic adaptations during pregnancy. We previously found that exercise influences maternal-foetal circulating cytokines (IL-1 beta, IL-6, IL-8, IL-10, TNF-alpha). This study investigated i) the influence of an exercise training programme during pregnancy on metabolic markers (glycaemic and lipid markers, and C-reactive protein) in maternal, and cord arterial and venous serum;and ii) whether these cytokines mediated the effects of exercise on metabolic markers. Eighty-eight pregnant women, divided into exercise (n = 44) and control (n = 44) groups, participated in this quasi-experimental study. The exercise group followed a 60-min 3 days/week concurrent (aerobic+resistance) exercise training. Glycaemic and lipid markers and C-reactive protein concentrations, and cytokines levels, were measured at weeks 17 and 34 and birth with standard biochemical methods and Luminex xMAP technology. Overall, exercise did not induce detectable changes in maternal metabolic markers during pregnancy, except for those exercisers whose IL-8 levels increased, where it was related to lower maternal total cholesterol (indirect effect= -9.1;95% CI= -24.6, -1.1) and low-density lipoprotein-cholesterol gains (-8.9;-21.9, -1.1). This suggests a mechanism by which exercise may optimise lipid metabolism regulation. Moreover, exercise was related to lower cord arterial serum glucose levels. Further research, especially concerning foetal metabolism, is necessary.

关键词： Immunology   Inflammation   Inflammatory bowel disease   Innate immunity   Monocytes  

摘要： Preclinical and clinical observations indicate that the probiotic Lactobacillus rhamnosus GG (LGG) can modulate colonic inflammation. However, the underlying mechanisms have not been explored in depth. Here, we demonstrate that oral administration of live LGG alleviated inflammatory colitis by increasing IL-10 expression in intestinal Ly6C⁺ monocytes. Mechanistically, LGG induced IL-10 production via the stimulator of IFN genes (STING)/TBK1/NF-κB (RELA) signaling pathway in intestinal Ly6C⁺ monocytes, enhancing their immune-suppressive function. Elevated IL-10 subsequently activated IL-10 signaling in Ly6C⁺ monocytes, resulting in an IL-10–based autocrine regulatory loop and inhibition of proinflammatory cytokine production. Furthermore, LGG shifted the gut microbial community and its metabolic functions, leading to intestinal immune responses against colitis. Fecal microbiota transplantation from LGG-colonized mice alleviated immune checkpoint blockade–associated colitis. Our findings highlight the importance of STING signaling in IL-10–dependent antiinflammatory immunity and establish an empirical basis for developing oral administration of live LGG as an efficient and safe therapeutic strategy against inflammatory colitis. Copyright: © 2025, Si et al.

摘要： In this issue of Developmental Cell, Tang et al. identify CD74^high neutrophils as a subpopulation promoted by IL-8 in the tumor microenvironment of non-small lung cancer (NSCLC). These CD74^high neutrophils support anti-tumor T cell responses and enhance the efficacy of anti-PD-1 immunotherapy and targeted therapy in NSCLC. © 2025 Elsevier Inc.

摘要： FAM210B (family with sequence similarity 210 member B) is a novel protein that has been linked to tumor development. However, its role and underlying mechanisms in lung adenocarcinoma (LUAD) progression remain largely unexplored. In this study, FAM210B was observed to be down-regulated in LUAD cells. Analyses of public datasets revealed that decreased expression of FAM210B predicts poor survival. Accordingly, in vitro and in vivo studies have confirmed the inhibitory role of FAM210B on the growth and tumor metastasis of LUAD cells. RNA-seq analysis further indicated that FAM210B plays a role in regulating innate immune-related signaling pathways in LUAD cells, particularly involving the production of type I interferon (IFN-alpha/beta). Specifically, FAM210B activates STAT1/IRF9/IFIT3 axis by upregulating IFN-alpha/beta expression, leading to the inhibition of proliferation and migration of LUAD cells. Furthermore, TOM70 (Translocase of outer mitochondrial membrane 70, also named as TOMM70) has been identified as a functional interacting partner of FAM210B in its modulation on the expression of IFN-alpha/beta, as well as the proliferative and metastatic phenotypes of LUAD cells. In conclusion, our study indicates that FAM210B is an important suppressor of cellular viability and mobility during lung cancer progression.

摘要： The contribution of IL-10 secreted by tumoral B cells to the progression and shaping of the microenvironment in diffuse large B-cell lymphoma (DLBCL) with activated B-cell (ABC) phenotype is not yet completely understood. To shed light on this issue, we generated an immunocompetent mouse model of ABC-DLBCL with conditional knock-out of IL-10 specifically in malignant B cells. Paradoxically, these mice had significantly worse overall survival when left untreated, but experienced increased sensitivity to conventional anti-CD20 immunotherapy or regulatory T cell (Treg) depletion. We identified various immunomodulatory mechanisms involved in this behavior. In particular, we show that IL-10-deficient lymphomas acquire a highly immunosuppressed and T-cell exhausted microenvironment with increased angiogenesis that results in a more aggressive phenotype, refractory to PD-1 immune checkpoint blockade (ICB). However, the response of IL-10-deficient mice to anti-CD20 immunotherapy was greatly enhanced by upregulation of calcium channels in B cells. In general, IL-10 autocrine signaling promotes survival of malignant B cells, while the paracrine action of B cell-derived IL-10 maintains an immunoreactive microenvironment that influences the efficacy of emerging immunotherapy strategies aimed at the lymphoma microenvironment (LME). Furthermore, IL-10-associated transcriptional signatures derived from our studies may correctly predict clinical outcomes of DLBCL patients treated with R-CHOP. Thus, our work provides important functional and mechanistic insights into the role of B cell-derived IL-10 in the biology of ABC-DLBCL.

关键词： CD19+ lymphocytes   CD4+ lymphocytes   CD8+ lymphocytes   early diagnosis   interleukin-7   lymphocytes   natural killer T cells   personalized medicine   sepsis   septic shock  

摘要： : Sepsis triggers a complex immune response, disrupting the balance between pro- and anti-inflammatory signals and causing widespread immune cell apoptosis. Interleukin 7 (IL-7) is emerging as one of the most promising immunoadjuvants to boost host immunity during the immunosuppressive phase of the disorder. This study aimed to investigate the dynamics of endogenous plasma levels of IL-7 during sepsis and septic shock, correlating its levels with lymphopenia and various lymphocyte subtypes, including CD4+ and CD8+ T cells, B cells, and natural killer T cells (NKT), in both survivors and non-survivors. : This prospective observational study included 87 critically ill patients. We categorized the patients into four subgroups based on their diagnosis (sepsis or septic shock) and survival status (survivors and non-survivors). The parameters were monitored on day 1 (when sepsis was diagnosed according to the Sepsis-3 Consensus) and again on day 5. Eighty-two healthy volunteers were included as a control group to establish the cut-off values for IL-7. : Statistical analysis revealed a significant difference in median values between days 1 and 5 for lymphocytes ( = 0.01) and NKT cells ( = 0.01), observed only in sepsis survivors. In the group of sepsis survivors, we observed a negative correlation between IL-7 levels and NKT cells but only on day 1. Additionally, we identified negative correlations between Th cells (CD4+) and Tc cells (CD8+) on both day 1 and day 5. In the group of sepsis non-survivors, we observed a positive correlation between IL-7 and B cells (CD19+) but only on day 1. We also identified a negative correlation between Th cells (CD4+) and Tc cells (CD8+) on day 1. In the group of septic shock survivors, we did not observe any correlation between IL-7 levels and other parameters studied on day 1 or day 5. We identified a negative correlation between Th cells (CD4+) and Tc cells (CD8+) on both day 1 and day 5, a negative correlation between Th cells (CD4+)

关键词： IL-6   TNF-α   hypertension   middle-aged men   overweight-related hypertension   pathophysiology   serum leptin   testosterone   total cholesterol  

摘要： BACKGROUND/OBJECTIVES:One of the major causes of hypertension (HT) is the transition of normal weight (NW) status to overweight (OW) status and obesity in a population, which leads to cardiovascular disease (CVD) and other disorders. A variety of factors/variables are involved in the development of HT and OW-related hypertension (OHT). However, we planned to investigate the pathophysiological role of serum leptin (Lep), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), total cholesterol (TC) and serum testosterone (ST) in OHT in middle-aged men. METHODS:We consulted three groups of middle-aged men (age: 51-60 years)-an HT group (n: 97, high normal weight (HNW), body mass index (BMI): 23-24.9 kg/m); an OHT group (n: 97, high overweight (HOW), BMI: 28-29.9 kg/m) and a normal control group (NC, n: 98, HNW)-to investigate the variations in and correlations of Lep, IL-6, TNF-α, ST, TC and other variables. RESULTS:Significant variations were obtained for the comparisons of TNF-α, Lep, ST and TC for the patient groups. OHT vs. NC showed a significant difference for ST. OHT vs. NC and OHT vs. HT had significant variations for IL-6. Significant changes were obtained for the serum levels of TNF-α, Lep, IL-6, ST and TC among groups. Significant and positive linear associations were obtained for TNF-α, Lep, TC and IL-6. Significant and negative linear associations were found for ST plotted against Lep, TNF-α and IL-6. CONCLUSIONS:The current report provides pathophysiological evidence of the interactive role of serum Lep, TNF-α, ST, TC and IL-6 in middle-aged men with HT and OHT. We suggest that the changes we noted in the present study would be helpful for further BMI-based studies in various subcategories of NW, OW and obese subjects with/without HT.