肿瘤细胞治疗研究
英文原题：Distinct tumor immune microenvironmental landscapes drive divergent immunotherapy responses in glioblastoma.
GBM 包含 3 种功能性 TIME 亚型，其血管-免疫景观存在差异，需要亚型特异性的治疗策略。
**背景：**免疫疗法已改善多种癌症的治疗结局，但对胶质母细胞瘤（GBM）仍基本无效。本研究通过对肿瘤免疫微环境（TIME）及相关血管特征进行功能分型，探究能否为GBM合理制定个体化免疫治疗方案。 **方法：**研究采用单细胞及单核RNA测序、多重免疫组化和流式细胞术，对人和小鼠GBM中的TIME亚型进行界定；并在原位同系GBM小鼠模型中评估抗血管生成及免疫调节疗法的反应，包括CD40激动剂、PD-L1靶向治疗和PI3K抑制。 **结果：**在人和小鼠GBM中均识别出三种具有不同血管—免疫特征的功能性TIME亚型。TIME低型肿瘤免疫细胞稀少或呈“免疫荒漠”，血管渗漏；TIME中型GBM具有中等程度免疫浸润、显著血管生成和活跃免疫反应；TIME高型肿瘤则有大量免疫抑制性髓系细胞浸润及功能失调的T细胞。代表性小鼠模型显示，各亚型对抗血管生成免疫调节疗法的敏感性不同。TIME低型GBM中T细胞活化短暂，随后因髓系细胞驱动的免疫抑制和间质转化而复发。TIME中型肿瘤对多种抗血管生成免疫调节疗法的反应最有利。TIME高型GBM总体耐药，但靶向髓系细胞的PI3K抑制可提高疗效。相反，CD40激动剂治疗通过增强血管生成、加重免疫抑制、损害T细胞功能、减少NK细胞募集并促进肿瘤增殖，反而降低生存率。 **结论：**GBM包含三种血管—免疫景观不同的功能性TIME亚型，需要采用亚型特异的治疗策略。TIME中型肿瘤最适合接受免疫疗法；TIME低型肿瘤接受抗血管生成免疫调节治疗后仅有短暂获益；TIME高型肿瘤则对治疗耐药，若不针对性逆转髓系免疫抑制，结局甚至可能恶化。
BACKGROUND: Immunotherapies have improved outcomes in many cancers but remain largely ineffective in glioblastoma (GBM). We investigated whether immunotherapy could be rationally tailored to GBM by functionally subtyping the tumor immune microenvironment (TIME) and associated vascular landscapes. METHODS: Single-cell and single-nucleus RNA sequencing, multiplex immunohistochemistry, and flow cytometry were used to define TIME subtypes in human and murine GBMs. Therapeutic responses to anti-angiogenic and immunomodulatory therapies, including CD40 agonist, PD-L1, and PI3K / inhibition, were assessed in orthotopic syngeneic GBM mouse models. RESULTS: Three distinct functional TIME subtypes with unique vascular-immune landscapes were identified in human and murine GBM. TIME-low tumors were immune-low/deserted with a leaky vasculature. TIME-med GBM exhibited intermediate immune-infiltration, prominent angiogenesis, and active immune responses. TIME-high tumors showed dense infiltration of immunosuppressive myeloid cells and dysfunctional T cells. Representative mouse models demonstrated subtype-specific sensitivities to anti-angiogenic immunomodulating therapies. TIME-low GBMs exhibited transient T-cell activation but relapsed due to myeloid-driven immunosuppression and mesenchymal transition. TIME-med tumors displayed the most favorable responses across anti-angiogenic immunomodulating therapies. TIME-high GBMs were largely resistant, although therapeutic efficacy improved with myeloid-targeted PI3K inhibition. In contrast, CD40 agonist therapy worsened survival by enhancing angiogenesis, amplifying immunosuppression, impairing T cell function, reducing NK-cell recruitment, and promoting tumor propagation. CONCLUSIONS: GBM comprises 3 functional TIME subtypes with divergent vascular-immune landscapes that require subtype-specific therapeutic strategies. TIME-med tumors are most amenable to immunotherapies. TIME-low tumors derive transient effects with anti-angiogenic immunomodulating therapies, and TIME-high are resistant or even experience worse outcome without targeted reversal of myeloid immunosuppression.
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