PDF(Pubmed)
Abstract：
Immune checkpoint inhibitors have revolutionized anti-tumor therapy, notably improving treatment responses in various tumors. However, many patients remain non-responsive and do not experience benefits. Given that Toll-like receptors (TLRs) can counteract tumor immune tolerance by stimulating both innate and adaptive immune responses, TLR agonists are being explored as potential immune adjuvants for cancer treatment. In this study, we assessed the potential of enhancing the efficacy of immune checkpoint inhibitors by activating innate immunity with a TLR5 agonist. In a mouse tumor model, combination therapy with TLR5 agonist and anti-PD-1 significantly inhibited tumor growth. The TLR5 agonist shifted the balance from M2-like to M1-like macrophages and upregulated the expression of co-stimulatory molecules in macrophages. Furthermore, TLR5 agonist promoted the activation and tumor infiltration of CD8+ T cells. As a result, the TLR5 agonist augmented the anti-tumor efficacy of anti-PD-1, suggesting its potential in modulating the tumor microenvironment to enhance the anti-tumor response. Our findings point toward the possibility of optimizing immune checkpoint inhibitor therapy using TLR5 agonists.
摘要：
免疫检查点抑制剂彻底改变了抗肿瘤治疗，显着改善各种肿瘤的治疗反应。然而,许多患者仍无反应,没有获益.鉴于Toll样受体（TLR）可以通过刺激先天和适应性免疫反应来抵消肿瘤免疫耐受，TLR激动剂正在被探索作为用于癌症治疗的潜在免疫佐剂。在这项研究中,我们评估了用TLR5激动剂激活先天免疫增强免疫检查点抑制剂疗效的潜力.在小鼠肿瘤模型中，TLR5激动剂和抗PD-1联合治疗可显著抑制肿瘤生长。TLR5激动剂将平衡从M2样巨噬细胞转变为M1样巨噬细胞,并上调巨噬细胞中共刺激分子的表达。此外，TLR5激动剂促进CD8+T细胞的活化和肿瘤浸润。因此,TLR5激动剂增强了抗PD-1的抗肿瘤功效,表明其在调节肿瘤微环境以增强抗肿瘤反应方面的潜力.我们的发现指出了使用TLR5激动剂优化免疫检查点抑制剂治疗的可能性。
