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

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...

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Published inbioRxiv
Main Authors Zhang, Allen W, Mcpherson, Andrew, Milne, Katy, Kroeger, David R, Hamilton, Phineas T, Miranda, Alex, Funnell, Tyler, Laan, Sonya, Cochrane, Dawn R, Lim, Jamie L P, Yang, Winnie, Roth, Andrew, Smith, Maia A, De Souza, Camila, Ho, Julie, Kane Tse, Zeng, Thomas, Shlafman, Inna, Mayo, Michael R, Moore, Richard, Failmezger, Henrik, Heindl, Andreas, Yi Kan Wang, Bashashati, Ali, Brown, Scott D, Lai, Daniel, Wan, Adrian N C, Nielsen, Cydney B, Bouchard-Cote, Alexandre, Yuan, Yinyin, Wasserman, Wyeth W, C Blake Gilks, Karnezis, Anthony N, Aparicio, Samuel, Mcalpine, Jessica N, Huntsman, David G, Holt, Robert A, Nelson, Brad H, Shah, Sohrab P
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 04.10.2017
Subjects
B-cell receptor
CD8 antigen
Cloning
Cytotoxicity
Foldback
Gene expression
Genomes
Image processing
Immunohistochemistry
Lymphocytes
Lymphocytes B
Lymphocytes T
Metastases
Ovarian cancer
Tumor-infiltrating lymphocytes
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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.
DOI:10.1101/198101