Tumour and local lymphoid tissue interaction determines prognosis in high grade serous ovarian cancer

Tertiary lymphoid structure (TLS) is an ectopic lymphoid organ found in some tumours. The presence of TLS is recently proposed as a predictive biomarker for immune checkpoint inhibitors (ICI) in mutation-driven tumours. TLS is also associated with prognosis in copy number-driven tumours, including high grade serous ovarian cancer (HGSOC), although the function of TLS and its interaction with copy-number alterations in HGSOC is not fully understood. In the current study, we comprehensively analyse immune profile, copy number profile and quantitative imaging profile from 242 HGSOC patients (HH cohort), and combine these with two public single cell RNA-sequencing datasets (Lambrechts cohorts; n=9, 29,999 cells). TLS-high HGSOC patients show significantly better progression free survival in both HH and TCGA cohorts. We show that presence of TLS in HGSOC tumours is associated with B-cell maturation, resulting in higher and more specific immunoglobulin production; TLS also leads to more cytotoxic tumour-specific T-cells activation and proliferation. Through integrated analysis of single cell RNA-sequencing and whole exome sequencing data, we reveal that the copy number loss of IL15 and CXCL10 may limit TLS formation in HGSOC; we also propose a list of genes that may dysregulate TLS function. A candidate gene, DCAF15, is found to confer resistance to NK-mediated cytotoxicity in HGSOC cell lines. Lastly, we develop a radiomics-based signature to predict presence of TLS, which independently predicts PFS in both HGSOC patients and ICI-treated NSCLC patients. Overall, we reveal that TLS coordinates intratumoural B-cell and T-cell response against HGSOC tumour, while cancer genome evolves to counteract TLS formation and function.三级淋巴结构（Tertiary lymphoid structure）是一类存在于部分肿瘤组织中的异位淋巴器官。近期有研究提出，TLS的存在可作为突变驱动型肿瘤患者接受免疫检查点抑制剂（immune checkpoint inhibitors, ICI）治疗的预测生物标志物。TLS亦与拷贝数驱动型肿瘤的预后密切相关，其中包括高级别浆液性卵巢癌（high grade serous ovarian cancer, HGSOC），但目前学界尚未完全阐明TLS的功能及其与HGSOC中拷贝数变异的相互作用机制。本研究对242名HGSOC患者（HH队列）的免疫组学特征、拷贝数特征及定量成像特征进行了全面分析，并结合了两项公开的单细胞RNA测序（single cell RNA-sequencing）数据集（Lambrechts队列；n=9, 29,999个细胞）。TLS高表达的HGSOC患者在HH队列与TCGA队列中均表现出显著更长的无进展生存期（progression free survival, PFS）。研究发现，HGSOC肿瘤组织中TLS的存在与B细胞成熟密切相关，可促进免疫球蛋白的产生且特异性更强；同时，TLS还能更强地激活并增殖肿瘤特异性细胞毒性T细胞。通过整合单细胞RNA测序与全外显子组测序（whole exome sequencing）数据，本研究揭示IL15与CXCL10的拷贝数缺失可能会抑制HGSOC中TLS的形成；同时，本研究还筛选出了一批可能失调TLS功能的基因。候选基因DCAF15可在HGSOC细胞系中赋予肿瘤细胞抵抗NK细胞介导的细胞毒性的能力。最后，本研究构建了基于放射组学的特征标签，用于预测肿瘤组织中TLS的存在情况，该标签可独立预测HGSOC患者以及接受ICI治疗的非小细胞肺癌（non-small cell lung cancer, NSCLC）患者的无进展生存期。综上，本研究阐明了TLS可协同调控肿瘤内B细胞与T细胞针对HGSOC的免疫应答，而肿瘤基因组则通过演化过程抵消TLS的形成与功能。