肿瘤细胞治疗研究
英文原题：Expansion and CAR engineering of granulocyte-monocyte progenitors for cellular immunotherapy.
这些发现确立了可扩增GMP作为工程化免疫治疗的可扩展平台。
工程化巨噬细胞在肿瘤免疫治疗中具有前景，但受限于体外扩增差、遗传可操作性和过继转移后的生物分布。在此，我们开发了确定的培养条件，能够长期扩增小鼠和人类粒细胞-单核细胞祖细胞（GMPs），同时保持祖细胞身份和髓系潜能，从而将GMPs确立为可再生的工程化平台。在机制上，我们鉴定出髓过氧化物酶是GMP增殖的调节因子。扩增后的GMPs易于工程化改造，并且在转移后定植造血龛并产生供体来源的髓系生成，从而恢复慢性肉芽肿病小鼠的抗菌防御，并产生大量肿瘤浸润巨噬细胞。用嵌合抗原受体（CARs）工程化改造的GMPs可抑制CD19阳性白血病和人类表皮生长因子受体2（HER2）阳性实体瘤。我们进一步引入了一种包含免疫球蛋白G（IgG）Fc结构域的CAR，该结构域可招募表达Fc受体的宿主吞噬细胞，使T细胞能够在主要组织相容性复合体（MHC）不匹配的情况下被致敏，并增强在免疫健全同种异体癌症模型中的疗效。总之，这些发现将可扩增的GMPs确立为工程化免疫治疗的可规模化平台。
Engineered macrophages are promising for tumor immunotherapy but are limited by poor ex vivo expansion, genetic tractability, and biodistribution after transfer. Here, we develop defined culture conditions that enable long-term expansion of mouse and human granulocyte-monocyte progenitors (GMPs) while preserving progenitor identity and myeloid potential, establishing GMPs as a renewable engineering platform. Mechanistically, we identify myeloperoxidase as a regulator of GMP proliferation. Expanded GMPs are readily engineered and, after transfer, seed hematopoietic niches and generate donor-derived myelopoiesis that restores antibacterial defense in chronic granulomatous disease mice and yields abundant tumor-infiltrating macrophages. GMPs engineered with chimeric antigen receptors (CARs) suppress CD19-positive leukemia and human epidermal growth factor receptor 2 (HER2)-positive solid tumors. We further introduce a CAR incorporating an immunoglobulin G (IgG) Fc domain that recruits host Fc receptor-expressing phagocytes, enables T cell priming across major histocompatibility complex (MHC) mismatch, and enhances efficacy in immunocompetent allogeneic cancer models. Together, these findings establish expandable GMPs as a scalable platform for engineered immunotherapy.
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