CXCL13 塑造免疫活性肿瘤微环境，并增强 PD-1 检查点阻断在高级别浆液性卵巢癌中的疗效。
CXCL13 shapes immunoactive tumor microenvironment and enhances the efficacy of PD-1 checkpoint blockade in high-grade serous ovarian cancer.
机构信息
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.
Department of Biochemistry and Molecular Biology, Fudan University School of Basic Medical Sciences, Shanghai, China.
出版信息
J Immunother Cancer. 2021 Jan;9(1). doi: 10.1136/jitc-2020-001136.
BACKGROUND
Most patients with high-grade serous ovarian cancer (HGSC) lack an effective response to immune checkpoint blockade, highlighting the need for more knowledge about what is required for successful treatment. As follicular cytotoxic CXCR5CD8 T cells are maintained by reinvigoration by immune checkpoint blockade in tumors, we attempted to reveal the relationship between CXCR5CD8 T cells and the tumor microenvironment to predict immunotherapy responses in HGSC.
METHODS
264 patients with HGSC from two cohorts and 340 HGSC cases from The Cancer Genome Atlas cohort were enrolled. Ex vivo and in vivo studies were conducted with human HGSC tumors and murine tumor models. The spatial correlation between CXC-chemokine ligand 13 (CXCL13), CXCR5, CD8, and CD20 was evaluated by immunohistochemistry and immunofluorescence. Survival was compared between different subsets of patients using Kaplan-Meier analysis. The therapeutic effect of CXCL13 and programmed cell death-1 (PD-1) blockade was validated using human HGSC tumors and murine models.
RESULTS
High CXCL13 expression was associated with prolonged survival. Tumors with high CXCL13 expression exhibited increased infiltration of activated and CXCR5-expressing CD8 T cells. Incubation with CXCL13 facilitated expansion and activation of CXCR5CD8 T cells ex vivo. CXCR5CD8 T cells appeared in closer proximity to CXCL13 in tumors and chemotaxis towards CXCL13 in vitro. The combination of CXCL13, CXCR5, and CD8 T cells was an independent predictor for survival. In addition, CXCL13 was associated with clusters of CD20 B cells. CD20 B cells predicted better patient survival in the presence of CXCL13. Histological evaluation highlighted colocalization of CXCL13 with tertiary lymphoid structures (TLSs). TLSs carried prognostic benefit only in the presence of CXCL13. CXCL13 in combination with anti-PD-1 therapy retarded tumor growth in a CD8 T-cell-dependent manner, resulting in increased infiltration of cytotoxic CD8 T cells and CXCR5CD8 T cells.
CONCLUSIONS
These data define a critical role of CXCL13 in shaping antitumor microenvironment by facilitating the maintenance of CXCR5CD8 T cells in TLSs and support a clinical investigation for a combination of CXCL13 and PD-1 blockade therapy in HGSC.
背景
大多数高级别浆液性卵巢癌（HGSC）患者对免疫检查点阻断缺乏有效反应，这凸显了需要更多了解成功治疗所需的条件。由于滤泡细胞毒性 CXCR5CD8 T 细胞在肿瘤中通过免疫检查点阻断的再激活得以维持，我们试图揭示 CXCR5CD8 T 细胞与肿瘤微环境之间的关系，以预测 HGSC 的免疫治疗反应。
方法
纳入了两个队列的 264 例 HGSC 患者和癌症基因组图谱队列的 340 例 HGSC 病例。用人 HGSC 肿瘤和鼠肿瘤模型进行了离体和体内研究。通过免疫组织化学和免疫荧光评估 CXC-趋化因子配体 13（CXCL13）、CXCR5、CD8 和 CD20 之间的空间相关性。使用 Kaplan-Meier 分析比较不同亚组患者的生存情况。使用人 HGSC 肿瘤和鼠模型验证了 CXCL13 和程序性细胞死亡蛋白 1（PD-1）阻断的治疗效果。
结果
高 CXCL13 表达与延长的生存相关。高 CXCL13 表达的肿瘤显示出更多的活化和 CXCR5 表达的 CD8 T 细胞浸润。离体孵育 CXCL13 促进了 CXCR5CD8 T 细胞的扩增和激活。CXCR5CD8 T 细胞在肿瘤中更接近 CXCL13，并在体外向 CXCL13 趋化。CXCL13、CXCR5 和 CD8 T 细胞的组合是生存的独立预测因子。此外，CXCL13 与 CD20 B 细胞簇相关。在存在 CXCL13 的情况下，CD20 B 细胞预测患者的生存更好。组织学评估突出了 CXCL13 与三级淋巴结构（TLSs）的共定位。只有在存在 CXCL13 的情况下，TLSs 才具有预后益处。CXCL13 联合抗 PD-1 治疗以依赖于 CD8 T 细胞的方式抑制肿瘤生长，导致细胞毒性 CD8 T 细胞和 CXCR5CD8 T 细胞的浸润增加。
结论
这些数据定义了 CXCL13 通过促进 TLS 中 CXCR5CD8 T 细胞的维持在塑造抗肿瘤微环境中的关键作用，并支持在 HGSC 中进行 CXCL13 和 PD-1 阻断联合治疗的临床研究。
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