通过联合激活TLR和STING信号通路工程化炎性巨噬细胞进行肿瘤内免疫细胞转移展现了强有力的抗肿瘤活性。
Intratumoral adoptive transfer of inflammatory macrophages engineered by co-activating TLR and STING signaling pathways exhibits robust antitumor activity.
发表日期：2023 Aug 03
作者：
Junyong Yoon, Moonkyoung Jeong, Ji-Ho Park
来源：
Brain Structure & Function
摘要：
尽管嵌合抗原受体（CAR）T细胞在血液恶性肿瘤中取得了成功，但养育细胞疗法（ACT）在治疗实体肿瘤方面并不有效。在这里，我们开发了一种基于炎症巨噬细胞的ACT，以有效治疗实体肿瘤。我们通过共激活Toll样受体和干扰素基因刺激剂信号通路，使炎症巨噬细胞发挥其抗肿瘤活性，包括促炎细胞因子的分泌和共刺激分子的表达。工程改造后的巨噬细胞在其养育细胞疗法转移到抗炎症肿瘤微环境（TME）后，仍然保持炎症表型，而使用干扰素γ处理制备的常规炎症巨噬细胞会转化为抗炎症表型。在一个小鼠黑色素瘤模型中，通过肿瘤内注射工程改造后的巨噬细胞，显示出强大的肿瘤生长抑制作用，通过增加TME中的CD8+ T细胞和血液中的肿瘤抗原特异性CD8+ T细胞。这项研究表明，工程改造后的炎症巨噬细胞有望作为一种有效的ACT用于治疗实体肿瘤。©2023. 作者，独家授权给Springer Nature Switzerland AG。
Despite the success of chimeric antigen receptor (CAR) T cells in hematologic malignancies, adoptive cell therapy (ACT) has not been effective in treating solid tumors. Here, we developed an inflammatory macrophage-based ACT to effectively treat solid tumors. We engineered inflammatory macrophages to enhance their antitumor activities, including proinflammatory cytokine secretion and co-stimulatory molecule expression by co-activating toll-like receptor and stimulator of interferon genes signaling pathways. Engineered macrophages maintain an inflammatory phenotype after their adoptive transfer into the anti-inflammatory tumor microenvironment (TME), whereas conventional inflammatory macrophages prepared using interferon-γ treatment are repolarized to an anti-inflammatory phenotype. In a mouse melanoma model, intratumoral adoptive transfer of engineered macrophages showed robust tumor growth inhibition by increasing CD8+ T cells in the TME and tumor antigen-specific CD8+ T cells in the blood. This study demonstrated that engineered inflammatory macrophages have potential as an effective ACT for treating solid tumors.© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.