PO.CL05.13 · 临床研究
在卵巢癌小鼠模型中研究TLR4和TLR9驱动的免疫治疗对MyD88和NLRP3通路的调节
Investigating MyD88 and NLRP3 pathway modulation in a TLR4 and TLR9 driven immunotherapy in a murine model of ovarian cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
卵巢癌仍是最具破坏性的妇科恶性肿瘤之一，部分原因在于其免疫抑制性肿瘤微环境（TME）限制了免疫治疗的疗效。我们此前的工作表明，含有单磷酰脂质A（TLR4激动剂）和CpG（TLR9激动剂）的基于同基因癌细胞的免疫疗法可刺激癌症特异性免疫应答。这两种受体均通过MyD88发出信号以激活NF-κB并产生促炎细胞因子。这些通路还与NLRP3炎症小体相交汇，后者通过IL-1beta和IL-18放大炎症反应。受控的激活可增强抗肿瘤免疫，而失调的炎症小体信号则可能促进慢性炎症和免疫抑制。因此，理解MyD88和NLRP3如何塑造疫苗疗效至关重要。本研究评估了抑制MyD88和NLRP3如何影响我们卵巢癌免疫疗法的治疗效果。荷卵巢肿瘤的FVB小鼠接受了TLR激动剂硅化癌细胞免疫疗法，联合或不联合NLRP3抑制剂MCC950（10 mg/kg）或MyD88抑制剂TJM-2010（50 mg/kg）。抑制剂在每次免疫治疗剂量前后给药。通过光谱流式细胞术分析腹水免疫细胞，以评估免疫亚群和激活标志物。阻断NLRP3通路加速了卵巢癌的生长，而TLR激动剂免疫疗法则阻断了肿瘤进展并清除了已有肿瘤。NLRP3抑制降低了治疗疗效，肿瘤体积缩小但未能实现完全清除。在第12天，免疫治疗组的肿瘤负荷较PBS组显著减少（p = 0.0034）。免疫治疗+NLRP3抑制组也与PBS组存在差异，但获益减弱（p = 0.0091）。到第16天，BR5免疫治疗组和BR5+抑制剂组的肿瘤负荷较PBS组均显著减少（p < 0.0001）。这些发现表明NLRP3信号对TLR4/TLR9介导的抗肿瘤应答具有关键作用。正在进行的研究将阐明MyD88和NLRP3如何协调先天免疫激活，并指导未来的联合策略，以增强免疫并克服卵巢TME内的抑制。
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查看英文原文 English abstract
Ovarian cancer remains one of the most devastating gynecologic malignancies, partly due to an immunosuppressive tumor microenvironment (TME) that limits immunotherapy efficacy. Our previous work showed that syngeneic cancer cell-based immune therapy containing monophosphoryl lipid A (TLR4 agonist) and CpG (TLR9 agonist) stimulates cancer-specific immune responses. Both receptors signal through MyD88 to activate NF-κB and pro-inflammatory cytokine production. These pathways also intersect with the NLRP3 inflammasome, which amplifies inflammation through IL-1beta and IL-18. Controlled activation may enhance antitumor immunity, whereas dysregulated inflammasome signaling can promote chronic inflammation and immune suppression. Understanding how MyD88 and NLRP3 shape vaccine efficacy is therefore essential.This study evaluates how inhibition of MyD88 and NLRP3 affects the therapeutic efficacy of our ovarian cancer immune therapy. FVB mice bearing ovarian tumors received TLR-agonist silicified cancer cell immunotherapy with or without the NLRP3 inhibitor MCC950 (10 mg/kg) or the MyD88 inhibitor TJM-2010 (50 mg/kg). Inhibitors were administered around each immune-therapy dose. Ascitic immune cells were analyzed by spectral flow cytometry to assess immune subsets and activation markers.Blockade of the NLRP3 pathway accelerated ovarian cancer growth, while TLR-agonist immune therapy blocked tumor progression and cleared existing tumors. NLRP3 inhibition reduced therapeutic efficacy, tumor size decreased but complete clearance was not achieved. On Day 12, the immune-therapy group showed a significant reduction in tumor burden compared to PBS (p = 0.0034). The immune-therapy + NLRP3-inhibited group also differed from PBS but with diminished benefit (p = 0.0091). By Day 16, both BR5 immune-therapy and BR5 + inhibitor groups showed highly significant reductions in tumor burden compared to PBS (p < 0.0001).These findings demonstrate that NLRP3 signaling contributes critically to TLR4/TLR9-mediated antitumor responses. Ongoing studies will clarify how MyD88 and NLRP3 coordinate innate immune activation and guide future combination strategies to enhance immunity and overcome suppression within the ovarian TME.
AI Disclosure:ChatGPT was used to assist with editing and wording of this abstract. All scientific content, study design, and interpretation were generated and verified by the authors.
利益披露 Disclosure
A. V. Klas, None..
R. E. Serda, None.