肿瘤细胞治疗研究
英文原题：Development of a Patient-Derived 3D Immuno-Oncology Platform to Potentiate Immunotherapy Responses in Ascites-Derived Circulating Tumor Cells.
处于缓解期的患者常在治疗后 2 年内以更具侵袭性的疾病形式复发。
高级别浆液性卵巢癌（HGSOC）是妇科癌症死亡的主要原因。患者缓解后常在治疗结束两年内复发，且疾病侵袭性更强。免疫检查点阻断（ICB）等替代免疫肿瘤学（IO）策略，特别是靶向 PD-(L)1 信号轴的疗法，迄今疗效有限。本研究旨在利用表观遗传调节剂，通过离体患者来源 3D 平台和体内同系模型，最大化个体化 IO 联合治疗的获益。研究使用患者来源肿瘤腹水优化了一种离体 3D 筛选平台（PDOTS），该平台含自体免疫细胞和腹水来源循环肿瘤细胞，可快速测试个体化 IO 联合治疗。重要的是，3D 平台中的患者铂类化疗和聚 ADP 核糖聚合酶抑制剂应答能够重现临床应答。与临床试验结果相似，PDOTS 对 ICB 的应答通常较低，并与 CD3⁺ 免疫细胞及 EPCAM⁺/PD-L1⁺ 肿瘤细胞的比例呈正相关。因此，单用抗 PD-1/抗 PD-L1 免疫疗法时，应答最高的是系统性 CD3⁺ 表达较高、免疫细胞和肿瘤细胞 PD-L1 表达均高的患者来源 HGSOC 腹水。此外，表观遗传辅助药物预处理可显著增强离体 3D 筛选平台和体内肿瘤模型中的 ICB 疗效。研究还发现，表观遗传预处理会增加肿瘤分泌多种已知可增强 T 细胞和 NK 细胞活化及细胞毒性的关键细胞因子，包括 IL-6、IP-10（CXCL10）、KC（CXCL1）和 RANTES（CCL5）。此外，在患者来源 PDOTS 中，单独进行表观遗传预处理或与 ICB 联用，均可快速上调 CD69；CD69 是 CD4⁺ 和 CD8⁺ T 细胞早期活化的可靠标志。因此，这种功能性精准医疗方法可快速识别能够增强 ICB 疗效的个体化联合治疗方案，尤其有价值，因为目前在患者中测试大量潜在联合方案存在临床困难。
High-grade serous ovarian cancer (HGSOC) is responsible for the majority of gynecology cancer-related deaths. Patients in remission often relapse with more aggressive forms of disease within 2 years post-treatment. Alternative immuno-oncology (IO) strategies, such as immune checkpoint blockade (ICB) targeting the PD-(L)1 signaling axis, have proven inefficient so far. Our aim is to utilize epigenetic modulators to maximize the benefit of personalized IO combinations in ex vivo 3D patient-derived platforms and in vivo syngeneic models. Using patient-derived tumor ascites, we optimized an ex vivo 3D screening platform (PDOTS), which employs autologous immune cells and circulating ascites-derived tumor cells, to rapidly test personalized IO combinations. Most importantly, patient responses to platinum chemotherapy and poly-ADP ribose polymerase inhibitors in 3D platforms recapitulate clinical responses. Furthermore, similar to clinical trial results, responses to ICB in PDOTS tend to be low and positively correlated with the frequency of CD3+ immune cells and EPCAM+/PD-L1+ tumor cells. Thus, the greatest response observed with anti-PD-1/anti-PD-L1 immunotherapy alone is seen in patient-derived HGSOC ascites, which present with high levels of systemic CD3+ and PD-L1+ expression in immune and tumor cells, respectively. In addition, priming with epigenetic adjuvants greatly potentiates ICB in ex vivo 3D testing platforms and in vivo tumor models. We further find that epigenetic priming induces increased tumor secretion of several key cytokines known to augment T and NK cell activation and cytotoxicity, including IL-6, IP-10 (CXCL10), KC (CXCL1), and RANTES (CCL5). Moreover, epigenetic priming alone and in combination with ICB immunotherapy in patient-derived PDOTS induces rapid upregulation of CD69, a reliable early activation of immune markers in both CD4+ and CD8+ T cells. Consequently, this functional precision medicine approach could rapidly identify personalized therapeutic combinations able to potentiate ICB, which is a great advantage, especially given the current clinical difficulty of testing a high number of potential combinations in patients.
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