Treatment of solid tumors remains difficult, and therefore there has been increased focus on chimeric antigen receptor macrophages (CAR-M) to challenge solid tumors. However, CAR domain design of of adoptive cell therapy, which leads to differences in antitumor activity and triggered antitumor potential, remains poorly understood for macrophages. We developed an α1β1 integrin-mediated Fc-gamma receptor I (FcγRI) signaling component for CAR-M specific activation and its antitumor potential. We evaluated CAR-M effects with α1β1 integrin-mediated FcγRI signaling (ACT CAR-M) on the activation and antitumor phagocytic response of macrophages in vitro. Subcutaneous tumor model in BALB/c mice and carcinomatosis model in immunodeficient mice were used to test the antitumor effect of ACT CAR-M compared with CD3ζ CAR-M. The α1β1 integrin-mediated FcγRI signaling engagement of CAR-M was associated with enhanced macrophage activation and specific phagocytosis in primary human macrophages, and significantly improved tumor control and survival in multiple cancer models when compared to CD3ζ CAR-M. RNA-sequencing suggested that α1β1 integrin-mediated FcγRI engagement increased antitumor immunity by enhancing pro-inflammatory M1 phenotype-associated pathways, such as Toll-like receptor signaling, tumor necrosis factor signaling, and IL-17 signaling. α1β1 integrin-mediated FcγRI signaling engagement markedly enhanced antitumor effects of CAR-M immunotherapy, which is proposed as an advanced engineering CAR domain material to expand the clinical application of CAR-M.

中文翻译：

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一种工程化的 α1β1 整合素介导的 FcγRI 信号转导组分，用于控制增强的 CAR 巨噬细胞活化和吞噬作用


实体瘤的治疗仍然困难，因此越来越关注嵌合抗原受体巨噬细胞 （CAR-M） 来攻击实体瘤。然而，过继细胞疗法的 CAR 结构域设计导致抗肿瘤活性和触发抗肿瘤潜力的差异，对于巨噬细胞仍然知之甚少。我们开发了一种 α1β1 整合素介导的 Fc-γ 受体 I （FcγRI） 信号转导成分，用于 CAR-M 特异性激活及其抗肿瘤潜力。我们评估了 α1β1 整合素介导的 FcγRI 信号传导 （ACT CAR-M） 对体外巨噬细胞活化和抗肿瘤吞噬反应的 CAR-M 影响。采用 BALB/c 小鼠皮下肿瘤模型和免疫缺陷小鼠癌病模型检测 ACT CAR-M 与 CD3ζ CAR-M 相比的抗肿瘤效果。与 CD3ζ CAR-M 相比，CAR-M 的 α1β1 整合素介导的 FcγRI 信号参与与原代人巨噬细胞中巨噬细胞活化和特异性吞噬作用增强相关，并显着改善了多种癌症模型中的肿瘤控制和生存率。RNA 测序表明，α1β1 整合素介导的 FcγRI 参与通过增强促炎 M1 表型相关通路（如 Toll 样受体信号传导、肿瘤坏死因子信号传导和 IL-17 信号传导）来提高抗肿瘤免疫力。α1β1 整合素介导的 FcγRI 信号结合显著增强了 CAR-M 免疫疗法的抗肿瘤作用，被提议作为一种先进的工程 CAR 结构域材料，以扩大 CAR-M 的临床应用。