Advanced-stage high-grade serous ovarian cancer (HGSOC) remains a deadly gynecologic malignancy with high rates of disease recurrence and limited, effective therapeutic options for patients. There is a significant need to better stratify HGSOC patients into platinum refractory (PRF) vs. sensitive (PS) cohorts at baseline to improve therapeutic responses and survival outcomes for PRF HGSOC. We performed NanoString for GeoMx Digital Spatial Profile (G-DSP) multiplex protein analysis on PRF and PS tissue microarrays (TMAs) to study the bidirectional communication of cancer cells with immune cells in the tumor microenvironment (TME) of HGSOC. We demonstrate robust stratification of PRF and PS tumors at baseline using multiplex spatial proteomic biomarkers with implications for tailoring subsequent therapy. PS patients had elevated apoptotic and anti-tumor immune profiles, while PRF patients had dual AKT1 and WNT signaling with immunosuppressive profiles. We found that dual activity of AKT1 and WNT signaling supported the exclusion of immune cells, specifically tumor infiltrating lymphocytes (TILs), from the TME in PRF tumors, and this was not observed in PS tumors. The exclusion of immune cells from the TME of PRF tumors corresponded to abnormal endothelial cell structure in tumors with dual AKT1 and WNT signaling activity. We believe our findings provide improved understanding of tumor-immune crosstalk in HGSOC TME highlighting the importance of the relationship between AKT and WNT pathways, immune cell function, and platinum response in HGSOC.

中文翻译：

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铂难治性 HGSOC 的空间蛋白质组学研究表明 AKT 和 WNT 双重活性与免疫抑制肿瘤微环境有关

晚期高级别浆液性卵巢癌（HGSOC）仍然是一种致命的妇科恶性肿瘤，疾病复发率很高，且患者有效的治疗选择有限。迫切需要在基线时更好地将 HGSOC 患者分为铂类难治性 (PRF) 与敏感 (PS) 队列，以改善 PRF HGSOC 的治疗反应和生存结果。我们对 PRF 和 PS 组织微阵列 (TMA) 进行 NanoString for GeoMx 数字空间轮廓 (G-DSP) 多重蛋白质分析，以研究 HGSOC 肿瘤微环境 (TME) 中癌细胞与免疫细胞的双向通讯。我们使用多重空间蛋白质组生物标志物证明了 PRF 和 PS 肿瘤在基线时的稳健分层，这对调整后续治疗具有影响。PS 患者的细胞凋亡和抗肿瘤免疫特征升高，而 PRF 患者的 AKT1 和 WNT 双重信号传导具有免疫抑制特征。我们发现 AKT1 和 WNT 信号传导的双重活性支持从 PRF 肿瘤的 TME 中排除免疫细胞，特别是肿瘤浸润淋巴细胞 (TIL)，而在 PS 肿瘤中未观察到这一点。PRF 肿瘤 TME 中免疫细胞的排除对应于具有双重 AKT1 和 WNT 信号活性的肿瘤中异常的内皮细胞结构。我们相信我们的研究结果加深了对 HGSOC TME 中肿瘤免疫串扰的理解，强调了 HGSOC 中 AKT 和 WNT 通路、免疫细胞功能和铂反应之间关系的重要性。