Unraveling Tumor-Immune Heterogeneity in Advanced Ovarian Cancer Uncovers Immunogenic Effect of Chemotherapy [Pre&Post-Tx]

In metastatic cancer, the degree of heterogeneity of the tumor-immune microenvironment and its molecular underpinnings remain largely unstudied. To characterize the tumor-immune interface at baseline and during neoadjuvant chemotherapy in high-grade serous ovarian cancer (HGSOC), we performed immunogenomics analysis of treatment-naive and paired pre/post-chemotherapy treated samples. In treatment-naive HGSOC, we find that immune cell-excluded and inflammatory microenvironments co-exist within the same individuals and within the same tumor sites, indicating ubiquitous variability in immune cell infiltration. Analysis of tumor microenvironment cell composition, DNA copy number, mutations and gene expression showed that immune cell exclusion was associated with amplification of Myc target genes and increased expression of canonical Wnt signaling in treatment-naive HGSOC. Following neoadjuvant chemotherapy, increased natural killer cell infiltration and oligoclonal expansion of T cells were detected. We demonstrate that the tumor-immune microenvironment of advanced HGSOC is intrinsically heterogeneous and that chemotherapy induces local immune activation, suggesting that chemotherapy can potentiate the immunogenicity of immune-excluded HGSOC tumors. The goal of this particular experiment was quantify RNA expression using microarray technology, and then evaluate differences in the trasncirptomic landscape of treatment naïve metastatic high grade serous ovarian cancer. Samples analyzed: Described in figure 5a. 9 patients with 18 matched pre/post treatment tumor samples and 19 patients with 38 unmatched pre/post treatment tumor samples. Affymetrix mRNA microarrays were collected and analyzed for these samples.

在转移性癌症中，肿瘤免疫微环境的异质性程度及其分子基础仍未得到充分研究。为了表征高级别浆液性卵巢癌（high-grade serous ovarian cancer, HGSOC）基线状态及新辅助化疗期间的肿瘤免疫界面特征，我们对初治及配对的化疗前后样本进行了免疫基因组学分析。在初治HGSOC样本中，我们发现免疫细胞排斥型与炎症型微环境共存于同一患者乃至同一肿瘤病灶内，这表明免疫细胞浸润存在普遍的异质性。通过对肿瘤微环境细胞组成、DNA拷贝数、基因突变及基因表达的分析，我们发现初治HGSOC中免疫细胞排斥现象与MYC靶基因的扩增以及经典Wnt信号通路表达上调相关。新辅助化疗后，我们检测到自然杀伤细胞浸润增加以及T细胞的寡克隆扩增。本研究证实，晚期HGSOC的肿瘤免疫微环境存在固有异质性，且化疗可诱导局部免疫激活，这提示化疗能够增强免疫排斥型HGSOC肿瘤的免疫原性。本实验的研究目标为通过微阵列技术定量RNA表达水平，进而评估初治转移性高级别浆液性卵巢癌的转录组图谱差异。分析样本：如图5a所述。其中9例患者匹配有18份化疗前后肿瘤样本，19例患者拥有38份非匹配的化疗前后肿瘤样本。我们针对这些样本收集并分析了Affymetrix mRNA微阵列数据。