Telethon Kids Institute, The University of Western Australia, Nedlands, WA, Australia.
School of Molecular Sciences, The University of Western Australia, Crawley, WA, Australia.
Cell Rep Med. 2023 Jul 18;4(7):101113. doi: 10.1016/j.xcrm.2023.101113.
Recurrences frequently occur following surgical removal of primary tumors. In many cancers, adjuvant therapies have limited efficacy. Surgery provides access to the tumor microenvironment, creating an opportunity for local therapy, in particular immunotherapy, which can induce local and systemic anti-cancer effects. Here, we develop a surgically optimized biodegradable hyaluronic acid-based hydrogel for sustained intraoperative delivery of Toll-like receptor 3 agonist poly(I:C) and demonstrate that it significantly reduces tumor recurrence after surgery in multiple mouse models. Mechanistically, poly(I:C) induces a transient interferon alpha (IFNα) response, reshaping the tumor/wound microenvironment by attracting inflammatory monocytes and depleting regulatory T cells. We demonstrate that a pre-existing IFN signature predicts response to the poly(I:C) hydrogel, which sensitizes tumors to immune checkpoint therapy. The safety, immunogenicity, and surgical feasibility are confirmed in a veterinary trial in canine soft tissue tumors. The surgically optimized poly(I:C)-loaded hydrogel provides a safe and effective approach to prevent cancer recurrence.
手术后原发性肿瘤常常会复发。在许多癌症中，辅助疗法的疗效有限。手术可以进入肿瘤微环境，为局部治疗，特别是免疫治疗创造机会，免疫治疗可以诱导局部和全身抗癌作用。在这里，我们开发了一种经过手术优化的可生物降解透明质酸水凝胶，用于持续术中递送电镜受体 3 激动剂聚（I：C），并证明它在多种小鼠模型中显著降低了手术后的肿瘤复发率。从机制上讲，聚（I：C）诱导短暂的干扰素α（IFNα）反应，通过吸引炎症性单核细胞和耗尽调节性 T 细胞来重塑肿瘤/伤口微环境。我们证明，预先存在的 IFN 特征可预测对聚（I：C）水凝胶的反应，从而使肿瘤对免疫检查点治疗敏感。在兽医软组织肿瘤试验中证实了安全性、免疫原性和手术可行性。经手术优化的负载聚（I：C）水凝胶为预防癌症复发提供了一种安全有效的方法。
