Abstract:
Immunotherapy has emerged as a powerful weapon against lung cancer, yet only a fraction of patients respond to the treatment. Poly(I:C) (PIC) effectively triggers both innate and adaptive immunity. It can also induce immunogenic cell death (ICD) in tumor cells. However, its efficacy is hindered by its instability in vivo and limited cellular uptake. To address this, PIC is encapsulated in cRGD-functionalized polymersomes (t-PPIC), which significantly increases its stability and uptake, thus activating dendritic cells (DCs) and inducing apoptosis of lung tumor cells in vitro. In a murine LLC lung tumor model, systemic administration of t-PPIC effectively suppresses tumor growth and leads to survival benefits, with 40% of the mice becoming tumor-free. Notably, t-PPIC provokes stronger apoptosis and ICD in tumor tissue and elicits a more potent stimulation of DCs, recruitment of natural killer (NK) cells, and activation of CD8+ T cells, compared to free PIC and nontargeted PPIC controls. Furthermore, when combined with immune checkpoint inhibitors or radiotherapy, t-PPIC amplifies the antitumor immune response, resulting in complete regression in 60% of the mice. These compelling findings underscore the potential of integrin-targeted polymersomal PIC to enhance antitumor immunity by simultaneously inducing ICD and systemic immune activation.
摘要:
免疫疗法已经成为对抗肺癌的有力武器,然而,只有一小部分患者对治疗有积极反应。聚(I:C)有效地触发先天和适应性免疫。它还能够在肿瘤细胞中诱导免疫原性细胞死亡(ICD)。然而,其功效受到其体内不稳定性和有限细胞摄取的阻碍。为了解决这个问题,我们将聚(I:C)封装在cRGD靶向聚合物囊泡(t-PPIC)中,显著增加了它的稳定性和吸收,导致树突状细胞(DC)的重要激活和肺肿瘤细胞的凋亡。在鼠LLC肺肿瘤模型中,全身给药t-PPIC可有效抑制肿瘤生长,并带来显著的生存益处,40%的小鼠变得无肿瘤。值得注意的是,t-PPIC在肿瘤组织中引起更强的凋亡和ICD,并引起更有效的DC刺激,NK细胞的募集,激活CD8+T细胞,与游离聚(I:C)和非靶向PPIC对照相比。此外,当与免疫检查点抑制剂或放疗联合使用时,t-PPIC放大了抗肿瘤免疫反应,导致60%的小鼠完全消退。这些令人信服的发现强调了整合素靶向的聚合物体poly(I:C)通过同时诱导ICD和全身免疫激活来增强抗肿瘤免疫力的潜力。本文受版权保护。保留所有权利。