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