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关键词： IL-15 transpresentation   mRNA delivery   NK cell immunotherapy   ovarian cancer  

摘要： Ovarian cancer (OC) is the most lethal gynecological malignancy. As high numbers of Natural Killer (NK) cells in ascites associate with improved survival, the adoptive transfer of allogeneic NK cells is an attractive therapeutic strategy. An approach to further improve NK cell expansion and anti-tumor functionality post-infusion includes IL-15 transpresentation (transIL-15), which involves surface expression of the IL-15 cytokine bound to IL-15R alpha. However, others have substantiated that systemic administration of ALT/N-803, a soluble molecule mimicking transIL-15, leads to T cell-mediated rejection of the infused allogeneic NK cell product. In addition, whether transIL-15 induce superior expansion and functionality of our hematopoietic progenitor cell-derived NK cells (HPC-NK) remains understudied. Here, we propose to transfect OC cells with IL-15 and IL-15R alpha mRNA and evaluate HPC-NK cell stimulation in vitro. Co-transfection of both mRNAs resulted in surface co-expression of both components, thus mimicking the transIL-15. Importantly, co-culture of HPC-NK cells with transIL-15 OC cells resulted in superior proliferation, IFN gamma production, cytotoxicity and granzyme B secretion. Furthermore, we observed uptake of IL-15R alpha by HPC-NK cells when co-cultured with transIL-15 OC cells, which associates with NK cell long-term proliferation and survival. Superior killing and granzyme B secretion were also observed in transIL-15 OC spheroids. Our results demonstrate that local delivery of IL-15 and IL-15R alpha mRNA to OC tumors may be a safer strategy to boost HPC-NK cell therapy of OC through IL-15 transpresentation.

关键词： Chronic obstructive pulmonary disease   case-control study   single nucleotide polymorphisms   Chronic obstructive pulmonary disease   case-control study   IL18R1   single nucleotide polymorphisms  

摘要： Background: Although existing studies have identified some genetic loci associated with chronic obstructive pulmonary disease (COPD) susceptibility, many variants remain to be discovered. The aim of this study was to further explore the potential relationship between IL18R1 single nucleotide polymorphisms (SNPs) and COPD risk. Methods: Nine hundred and ninety-six subjects were recruited (498 COPD cases and 498 healthy controls). Five candidate SNPs of IL18R1 were selected and genotyped using MassARRAY iPLEX platform. Logistic regression analysis was performed to assess the association of these SNPs with COPD risk. Multifactor dimensionality reduction (MDR) software was applied to calculate the interaction of SNP-SNP on COPD risk. Results: IL18R1 rs9807989 (OR = 0.42, p < .001), rs3771166 (OR = 0.40, p < .001) and rs6543124 (OR = 0.44, p < .001) were associated with the reduced COPD risk, while rs2287037 (OR = 2.71, p < .001) and rs2058622 (OR = 2.06, p < .001) might be the risk-increasing factor for COPD occurrence in both the overall analysis and subgroup analysis (age, gender, drinking, and smoking). The best multi-locus model was the combination of rs2058622 and rs3771166. Conclusion: Our study provided a reference and basis for investigating the association of IL18R1 polymorphisms with COPD risk.

关键词： Psoriasis   biologic therapy   TNF inhibitors   interleukin inhibitors   IL-23  

摘要： IntroductionPsoriasis (PsO) is a common chronic, inflammatory, immune-mediated disease. In 2023, a 4.4% prevalence of PsO was reported in Portugal. Currently, Tumor Necrosis Factor inhibitors (TNFi) are the recommended first-line (1 L) biologic agents in Portugal given their lower cost. However, TNFi may not be suitable for several patients. In these patients, interleukin inhibitors (ILi) should be considered as they provide more effective outcomes and a better safety *** interviews with PsO experts were conducted to identify PsO biologic treatment needs, resulting in an online survey to explore clinical cases focused on subpopulations of PsO. A delphi study evaluated consensus on clinical criteria to initiate non-TNFi therapy in seven predefined subpopulations of *** study highlights the benefit of starting non-TNFi therapy in all PsO predefined subpopulations. Patients with infection risk, mild heart failure and associated comorbidities, autoimmune diseases and family history of demyelinating disease consensually benefit from starting non-TNFi therapy in 1 L. Several risks associated with latent tuberculosis, advanced age and oncological disease were also *** the existence of various risks associated with TNFi usage, this clinical perspective overview of Portuguese experts in PsO treatment emphasizes the need for a tailored therapeutic framework in the management of PsO.

关键词： Immunotherapy   immune checkpoint inhibitor   IL-2R agonist   T and NK cell exhaustion   IgG-binding domain  

摘要： As T and NK cell exhaustion is attributed to increased expression of immune checkpoints and decreased production of proliferative cytokines by these cells, immune checkpoint-targeted delivery of proliferative cytokines might induce robust and sustained antitumor immune responses. Here, the expression profile of NKG2A was first found to be narrower than that of PD-1 in tumor-infiltrated immune cells. Moreover, unlike PD-1, NKG2A was predominantly co-expressed with IL-2R beta gamma in tumor-infiltrated CD8+ T and NK cells, but not in Tregs, suggesting that NKG2A might be an ideal target for delivery of IL-2R beta gamma agonists to overcome T and NK exhausting. For NKG2A-targeted delivery of an IL-2R beta gamma agonist, a single molecule of de novo designed N215 endowed with Immunoglobin G(IgG)-binding ability was coupled to an antibody against NKG2A (alpha NKG2A) to produce alpha NKG2A-N215. NKG2A- and IL-2R beta gamma-binding were well preserved in alpha NKG2A-N215, allowing alpha NKG2A-N215 to act as both an immune checkpoint inhibitor and a T and NK cell stimulator. Intravenously injected alpha NKG2A-N215 predominantly induced expansion of tumor-infiltrated CD8+ T and NK cells while showing little stimulation of Tregs. Compared with the separate combination using alpha NKG2A and N215, alpha NKG2A-N215 exerted a greater antitumor effect in mice bearing MC38 or B16/F1 tumors. 50% of mice bearing MC38 tumors were cured by alpha NKG2A-N215, and long-term immunological memory against the tumor was induced in these mice. These results indicate that NKG2A is another ideal target for delivery of an IL-2R beta gamma agonist, and alpha NKG2A-N215, with specificities for both NKG2A and IL-2R beta gamma, might be developed as a novel agent for immunotherapy.

关键词： Calpain 2   hepatocellular carcinoma   IL-1 alpha   MDSCs   tumor microenvironment  

摘要： Tumor-promoting inflammation significantly impacts cancer progression, and targeting inflammatory cytokines has emerged as a promising therapeutic approach in clinical trials. Interleukin (IL)-1 alpha, a member of the IL-1 cytokine family, plays a crucial role in both inflammation and carcinogenesis. How IL-1 alpha is secreted in the tumor microenvironment has been poorly understood, and we previously showed that calpain 1 cleaves pro-IL-1 alpha for mature IL-1 alpha secretion, which exacerbates hepatocellular carcinoma by recruiting myeloid-derived suppressor cells. In this study, we report that calpain 2 also modulates IL-1 alpha secretion. Notably, a deficiency in calpain 2 resulted in enhanced hepatocellular carcinoma development within an IL-1 alpha-enriched tumor microenvironment. Further investigations revealed that calpain 2 deficiency increased calpain 1 expression, implying a compensatory mechanism between the two calpains. Mechanistically, calpain 2 deficiency led to increased expression of FoxO3, which is a forkhead transcription factor that promotes calpain 1 expression. Collectively, these results suggest that calpain 2 modulates calpain 1 expression, and therefore IL-1 alpha secretion through the induction of FoxO3, offering novel potential therapeutic targets for cancer treatment.

关键词： Parvimonas micra   host-microbe interaction   colorectal cancer   tumor microenvironment  

摘要： Parvimonas micra (Pm), a periodontal pathogen, has been implicated in the impairment of anti-tumor responses in colorectal cancer (CRC). The tumor microenvironment in CRC involves tumor-associated macrophages (TAMs), which are pivotal in modulating tumor-associated immune responses. The polarization of TAMs towards an M2-like phenotype promotes CRC progression by suppressing the immune system. However, the mechanisms by which Pm affects the progression of CRC remain inadequately elucidated. In this study, we explored the impact of Pm infection on CRC cell characteristics, including proliferation, chemoresistance, migration, and macrophage polarization. We found that Pm-infected THP-1-derived macrophages exhibited elevated interleukin-10 levels, a well-established M2 marker. Conditioned media from Pm-treated THP-1 cells significantly enhanced CRC cell proliferation, cisplatin resistance, and migration, and interleukin-8 was identified as a key factor. Consistent with the in vitro results, an azoxymethane/dextran sodium sulfate mouse model treated with oral Pm showed accelerated CRC tumor growth. These results offer mechanistic insights into the influence of Pm infection on tumor microenvironment in CRC through M2-like macrophage polarization. The identified pathways may serve as potential targets for therapeutic interventions for CRC.

关键词： Interferon gamma   Fas   tumor immunotherapy   membrane-bound form   secretory form  

摘要： Interferon gamma (IFN gamma) is well-known for its ability to stimulate immune cells in response to pathogen infections and cancer. To develop an effective cancer therapeutic vaccine, CT26 colon carcinoma cells were genetically modified to express IFN gamma either as a secreted form (sIFN gamma) or as a membrane-bound form. For the membrane-bound expression, IFN gamma was fused with Fas (mbIFN gamma/Fas), incorporating the extracellular cysteine-rich domains, transmembrane, and cytoplasmic domains of Fas. The tumor cells expressing sIFN gamma and mbIFN gamma/Fas showed slower growth rates compared to the mock-transfected cells. Furthermore, the tumorigenicity of the CT26 cells expressing mbIFN gamma/Fas was significantly lower than that of cells expressing sIFN gamma or the mock control. Remarkably, about 85% of the mice injected with the mbIFN gamma/Fas-expressing tumors remained tumor-free for over two months. Mice that rejected mbIFN gamma/Fas-expressing tumors developed systemic anti-tumor immunity against CT26 cells, which was characterized by enhanced levels of CD4+ and CD8+ T cells, as well as natural killer (NK) cells. Interestingly, splenocytes activated with the mbIFN gamma/Fas-expressing tumors exhibited higher cytotoxicity than those activated with tumor cells expressing sIFN gamma. These findings suggest that expressing the mbIFN gamma/Fas chimera in tumor cells could be a promising strategy for developing whole tumor cell vaccines or gene therapies for cancer immunotherapy.

关键词： Cancer immunotherapy   colorectal cancer   HLA class I match   HLA-A2.1   humanized cancer model   humanized mice   immune checkpoint inhibitors   KRAS   NRG-A2   pancreatic ductal adenocarcinoma  

摘要： Cancer immunotherapy promises to treat challenging cancers including KRAS-mutated colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC). However, pre-clinical animal models that better mimic patient tumor and immune system interactions are required. While humanized mice are promising vehicles for pre-clinical immunotherapy testing, currently used cancer models retain limitations, such as lack of a human thymus for human leukocyte antigen (HLA)-based education of human T cells. As cytotoxic T lymphocyte (CTL) activity underlies many immunotherapies, we developed more clinically relevant KRAS-mutated CRC and PDAC humanized cancer models using transgenic NRG-A2 mice expressing HLA-A2.1 to enable HLA-class-I match between mouse tissues (including the thymus), the humanized immune system and human tumors. Using these novel humanized cancer models and a CTL-mediated combination (immuno)therapy with clinical potential, we were able to recapitulate the complexity and therapy-induced changes reported in patient biopsies, demonstrating the use of these HLA-matched models for pre-clinical validation of novel immunotherapies.

关键词： Advanced cancer   HLA subtype   immune checkpoint   predictive biomarkers  

摘要： Specific shared HLA-I alleles were linked to the response to immune checkpoint blockade (ICB). We aimed to identify the HLA-A subtypes associated with maximum benefit from ICB. We compiled a clinical dataset of patients who underwent a CLIA-approved germline HLA status testing as part of various advanced immune and cell therapy trials undertaken at the Christie NHS Foundation Trust. A total of 285 patients were eligible for final analysis. We identified 15 HLA-A subtypes, the most common alleles being HLA-A02, HLA-A01, and HLA-A03. A02:01 showed a tumor lineage-specific distribution. One hundred and forty patients received ICB and had evaluable response status. Patients with A01 were associated with better clinical outcomes. No significant associations were observed between HLA-A subtypes and the incidence of immune-related adverse effects. HLA genotyping should be incorporated early in the diagnostic work-up of patients with solid cancers as a predictive and selective biomarker.

关键词： Severe asthma   anti-IL-5/IL-5(R) therapy   responder   remission   biomarker  

摘要： IntroductionPrevious studies of anti-IL-5/IL-5(R) therapies in severe asthma found that response was mainly predicted by indicators of good baseline disease control. However, long-term response predictors remain *** to anti-IL-5/IL-5(R) therapy in the well-characterised, real-life, international German Asthma Net (GAN) registry were analysed using regression analyses. Response was defined by >= 50% reduction in exacerbations or corticosteroid dose, super-response by a complete stop of both, and remission additionally by controlled asthma (ACT score >= 20).ResultsSeventy-seven percent of 347 patients (55% female, 56.6 +/- 12.3 years, follow-up 20.3 +/- 13 months) were responders and showed improved exacerbation rates, asthma control, and corticosteroid treatment reduction. Response was independently predicted by inhaled corticosteroid dose (odds ratio [OR] 1.5;p = 0.014), exacerbation rate (OR 1.2;p = 0.009), and treatment duration (OR 1.05, p = 0.023). Univariately, blood eosinophil counts notably predicted response (OR 12.4;p = 0.004). Super-response was inversely associated with corticosteroid dependence and depression. Remission was associated with the absence of systemic corticosteroids, better asthma control, and FEV1 in *** results underscore that long-term anti-IL-5/IL-5(R) therapy reduces exacerbation and corticosteroid burden, especially in patients with severe disease and high type 2 inflammatory burden. Contrastingly, low baseline corticosteroid use and markers of good asthma control predicted remission and super-responder status.