高级别浆液性卵巢癌(HGSOC)是大多数妇科癌症相关死亡的原因。处于缓解期的患者通常在治疗后2年内以更具侵袭性的疾病形式复发。替代免疫肿瘤学(IO)策略,例如靶向PD-(L)1信号轴的免疫检查点阻断(ICB),到目前为止,事实证明效率低下。我们的目标是利用表观遗传调节剂在离体3D患者衍生平台和体内同源模型中最大化个性化IO组合的益处。使用患者来源的肿瘤腹水,我们优化了离体3D筛选平台(PDOTS),使用自体免疫细胞和循环腹水来源的肿瘤细胞,快速测试个性化IO组合。最重要的是,患者对铂类化疗和聚ADP核糖聚合酶抑制剂在3D平台中的反应概括了临床反应.此外,与临床试验结果相似,PDOTS中对ICB的反应往往较低,并且与CD3免疫细胞和EPCAM/PD-L1肿瘤细胞的频率呈正相关。因此,在患者来源的HGSOC腹水中观察到单独使用抗PD-1/抗PD-L1免疫疗法观察到的最大反应,在免疫和肿瘤细胞中呈现高水平的系统性CD3+和PD-L1+表达,分别。此外,在离体3D测试平台和体内肿瘤模型中,用表观遗传佐剂引发极大地增强ICB。我们进一步发现,表观遗传引发诱导肿瘤分泌增加的几种关键细胞因子,已知增强T和NK细胞活化和细胞毒性,包括IL-6、IP-10(CXCL10)、KC(CXCL1),和RANTES(CCL5)。此外,在患者来源的PDOTS中单独的表观遗传引发以及与ICB免疫疗法组合诱导CD69的快速上调,CD69是CD4+和CD8+T细胞中免疫标志物的可靠早期激活。因此,这种功能精准医学方法可以快速识别能够增强ICB的个性化治疗组合,这是一个很大的优势,特别是考虑到目前在患者中测试大量潜在组合的临床困难。
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.