肿瘤细胞治疗研究
英文原题：IL-17-driven tumor cell-intrinsic inflammatory programming creates an immunotherapy-permissive microenvironment.
IL-17应答性、肿瘤细胞内在的炎症编程将肿瘤免疫微环境重塑为免疫治疗允许状态。这些发现确立了IL-17应答性肿瘤细胞炎症编程作为塑造免疫检查点敏感性的机制轴，并为生物标志物指导的免疫治疗策略提供了依据。
尽管免疫检查点抑制剂（ICIs）未能改善未经选择的卵巢癌人群的结局，但在少数卵巢透明细胞癌（OCCC）病例中观察到了客观缓解，这提示该组织学类型内存在生物学异质性以及一个尚未界定的免疫应答亚群。
我们对肿瘤浸润免疫细胞进行了免疫组化分析，并分析了人类OCCC队列的转录组数据。使用免疫健全的同系OCCC小鼠模型进行功能研究，以评估IL-17对肿瘤细胞炎症信号传导、免疫微环境重塑以及对免疫检查点阻断反应性的影响，包括对肿瘤浸润T细胞的单细胞RNA测序。
OCCC 表现出免疫稀疏的肿瘤微环境，CD4⁺ T 细胞相对富集。RORC 表达在 OCCC 中升高，但呈现肿瘤间异质性。在转录组数据（n = 180）中，IL17A 高表达亚群（5%）富集于 RORC 高表达部分内，表现出 T 细胞炎症基因表达谱，且不依赖于微卫星不稳定性和肿瘤突变负荷，但与生存无关。在机制上，IL-17 直接激活 OCCC 肿瘤细胞中 NF-κB 依赖性炎症程序，诱导参与 T 细胞募集和激活的细胞因子和趋化因子。在同基因模型中，IL-17 暴露增加了瘤内 CD4⁺ 和 CD8⁺ T 细胞浸润和激活。单细胞分析进一步揭示了 Th17/Tfh 样 CD4⁺ T 细胞和细胞毒性、非终末耗竭 CD8⁺ T 细胞的扩增。与这些变化一致，抗 PD-L1 治疗改善了 Th17 偏倚的部分嵌合体小鼠的生存。
BACKGROUND: While immune checkpoint inhibitors (ICIs) have failed to improve outcomes in unselected ovarian cancer populations, objective responses are observed in a minority of ovarian clear cell carcinoma (OCCC) cases, implying biological heterogeneity and a yet-undefined immunologically responsive subset within this histotype. METHODS: We performed immunohistochemical profiling of tumor-infiltrating immune cells and analyzed transcriptomic data from human OCCC cohorts. Functional studies were conducted using an immunocompetent syngeneic OCCC mouse model to assess the effects of IL-17 on tumor cell inflammatory signaling, immune microenvironment remodeling, and responsiveness to immune checkpoint blockade, including single-cell RNA sequencing of tumor-infiltrating T cells. RESULTS: OCCC exhibited an immune-sparse tumor microenvironment with relative enrichment of CD4⁺ T cells. RORC expression was elevated in OCCC but showed intertumoral heterogeneity. In the transcriptome data (n = 180), an IL17A high subset (5%), enriched within the RORC high fraction, exhibited a T cell-inflamed gene expression profile independent of microsatellite instability and tumor mutational burden, yet was not associated with survival. Mechanistically, IL-17 directly activated NF-κB-dependent inflammatory programs in OCCC tumor cells, inducing cytokines and chemokines involved in T-cell recruitment and activation. In the syngeneic model, IL-17 exposure increased intratumoral CD4⁺ and CD8⁺ T-cell infiltration and activation. Single-cell profiling further revealed expansion of Th17/Tfh-like CD4⁺ T cells and cytotoxic, non-terminally exhausted CD8⁺ T cells. Consistent with these changes, anti-PD-L1 therapy improved survival in Th17-biased partial chimera mice. CONCLUSIONS: IL-17-responsive, tumor cell-intrinsic inflammatory programming remodels the tumor immune microenvironment toward an immunotherapy-permissive state. These findings establish IL-17-responsive tumor cell inflammatory programming as a mechanistic axis shaping immune checkpoint sensitivity and provide a rationale for biomarker-guided immunotherapy strategies.
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