The interface of malignant and immunologic clonal dynamics in high-grade serous ovarian cancer

Summary
High-grade serous ovarian cancer exhibits extensive intratumoral heterogeneity coupled with widespread intraperitoneal disease. Despite this, metastatic spread of tumor clones is non-random, implying the existence of local microenvironmental factors that shape tumor progression. We interrogated the molecular interface between tumor-infiltrating lymphocytes (TIL) and cancer cells in 143 samples from 21 patients using whole-genome sequencing, immunohistochemistry, histologic image analysis, gene expression profiling, and T- and B-cell receptor sequencing. We identify 3 immunologic response categories, which frequently co-exist within individual patients. Furthermore, epithelial CD8+ TIL were inversely associated with malignant cell diversity, evidenced by subclonal neoepitope elimination and spatial tracking between tumor and T-cell clones. Intersecting mutational signatures and immune analysis showed that foldback inversion genomic aberrations lead to worse outcomes even in the presence of cytotoxic TIL (n=433). Thus, regional variation in immune contexture mirrors the pattern of intraperitoneal malignant spread, provoking new perspectives for treatment of this challenging disease.
Footnotes
Lead contact: S.P.S.
Subject Area
- Biochemistry (8792)
- Bioengineering (6495)
- Bioinformatics (23405)
- Biophysics (11769)
- Cancer Biology (9173)
- Cell Biology (13304)
- Clinical Trials (138)
- Developmental Biology (7426)
- Ecology (11392)
- Epidemiology (2066)
- Evolutionary Biology (15127)
- Genetics (10419)
- Genomics (14029)
- Immunology (9154)
- Microbiology (22132)
- Molecular Biology (8797)
- Neuroscience (47470)
- Paleontology (350)
- Pathology (1423)
- Pharmacology and Toxicology (2486)
- Physiology (3712)
- Plant Biology (8073)
- Synthetic Biology (2217)
- Systems Biology (6023)
- Zoology (1251)