Interfaces of Malignant and Immunologic Clonal Dynamics in Ovarian Cancer

Allen W. Zhang, Andrew McPherson, Katy Milne, David R. Kroeger, Phineas T. Hamilton, Alex Miranda, Tyler Funnell, Nicole Little, Camila P.E. de Souza, Sonya Laan, Stacey LeDoux, Dawn R. Cochrane, Jamie L.P. Lim, Winnie Yang, Andrew Roth, Maia A. Smith, Julie Ho, Kane Tse, Thomas Zeng, Inna ShlafmanMichael R. Mayo, Richard Moore, Henrik Failmezger, Andreas Heindl, Yi Kan Wang, Ali Bashashati, Diljot S. Grewal, Scott D. Brown, Daniel Lai, Adrian N.C. Wan, Cydney B. Nielsen, Curtis Huebner, Basile Tessier-Cloutier, Michael S. Anglesio, Alexandre Bouchard-Côté, Yinyin Yuan, Wyeth W. Wasserman, C. Blake Gilks, Anthony Karnezis, Samuel Aparicio, Jessica N. McAlpine, David G. Huntsman, Robert A. Holt, Brad H. Nelson, Sohrab P. Shah

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

High-grade serous ovarian cancer (HGSC) exhibits extensive malignant clonal diversity with widespread but non-random patterns of disease dissemination. We investigated whether local immune microenvironment factors shape tumor progression properties at the interface of tumor-infiltrating lymphocytes (TILs) and cancer cells. Through multi-region study of 212 samples from 38 patients with whole-genome sequencing, immunohistochemistry, histologic image analysis, gene expression profiling, and T and B cell receptor sequencing, we identified three immunologic subtypes across samples and extensive within-patient diversity. Epithelial CD8+ TILs negatively associated with malignant diversity, reflecting immunological pruning of tumor clones inferred by neoantigen depletion, HLA I loss of heterozygosity, and spatial tracking between T cell and tumor clones. In addition, combinatorial prognostic effects of mutational processes and immune properties were observed, illuminating how specific genomic aberration types associate with immune response and impact survival. We conclude that within-patient spatial immune microenvironment variation shapes intraperitoneal malignant spread, provoking new evolutionary perspectives on HGSC clonal dispersion. Integrated multi-region analysis of metastatic sites in patients with high-grade ovarian cancer highlights the connection between immune microenvironment variation and malignant spread, as well as the combinatorial prognostic value of immune and mutational features.

Original languageEnglish (US)
Pages (from-to)1755-1769.e22
JournalCell
Volume173
Issue number7
DOIs
StatePublished - Jun 14 2018
Externally publishedYes

Keywords

  • clonal evolution
  • clone
  • foldback inversion
  • HGSC
  • high-grade serous ovarian cancer
  • HLA
  • human leukocyte antigen
  • immunoediting
  • intratumoral heterogeneity
  • metastatic
  • mutation signature
  • tumor-infiltrating lymphocyte

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Zhang, A. W., McPherson, A., Milne, K., Kroeger, D. R., Hamilton, P. T., Miranda, A., Funnell, T., Little, N., de Souza, C. P. E., Laan, S., LeDoux, S., Cochrane, D. R., Lim, J. L. P., Yang, W., Roth, A., Smith, M. A., Ho, J., Tse, K., Zeng, T., ... Shah, S. P. (2018). Interfaces of Malignant and Immunologic Clonal Dynamics in Ovarian Cancer. Cell, 173(7), 1755-1769.e22. https://doi.org/10.1016/j.cell.2018.03.073