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.
高级别浆液性卵巢癌是导致妇科癌症相关死亡的主要原因。缓解期患者常在治疗后两年内复发，且疾病形式更具侵袭性。目前，靶向PD-(L)1信号轴的免疫检查点阻断等替代性免疫肿瘤学策略已被证实疗效有限。本研究旨在利用表观遗传调节剂，在离体三维患者源性平台及同源移植模型中最大化个性化免疫联合疗法的效益。通过患者源性肿瘤腹水，我们优化了离体三维筛选平台，该平台采用自体免疫细胞和循环腹水来源的肿瘤细胞，可快速测试个性化免疫联合方案。尤为重要的是，三维平台中患者对铂类化疗和聚腺苷二磷酸核糖聚合酶抑制剂的反应与临床反应高度一致。此外，与临床试验结果相似，三维平台中对免疫检查点阻断的反应普遍较低，且与CD3+免疫细胞频率及EPCAM+/PD-L1+肿瘤细胞频率呈正相关。因此，抗PD-1/抗PD-L1免疫单药治疗的最佳反应出现在具有高水平系统性CD3+（免疫细胞）和PD-L1+（肿瘤细胞）表达的HGSOC腹水样本中。值得注意的是，表观遗传佐剂预处理能显著增强离体三维测试平台及体内肿瘤模型中免疫检查点阻断的疗效。我们进一步发现，表观遗传预处理可诱导肿瘤分泌多种增强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，在患者源性三维平台中，表观遗传预处理单用或联合免疫检查点阻断治疗，均可快速上调CD4+和CD8+T细胞中可靠的早期免疫激活标志物CD69。因此，这种功能性精准医学方法能快速识别可增强免疫检查点阻断疗效的个性化联合治疗方案，在当前临床难以测试大量潜在联合方案的背景下具有显著优势。
肿瘤(癌症)患者之家