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Cell. 2018 Jun 14;173(7):1755-1769.e22. doi: 10.1016/j.cell.2018.03.073. Epub 2018 May 10.

Interfaces of Malignant and Immunologic Clonal Dynamics in Ovarian Cancer.

Author information

1
Department of Molecular Oncology, BC Cancer, Vancouver, BC V5Z 4E6, Canada; BC Children's Hospital Research, Vancouver, BC V5Z 4H4, Canada; Graduate Bioinformatics Training Program, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
2
Department of Molecular Oncology, BC Cancer, Vancouver, BC V5Z 4E6, Canada.
3
Deeley Research Centre, BC Cancer, Victoria, BC V8R 6V5, Canada.
4
Department of Molecular Oncology, BC Cancer, Vancouver, BC V5Z 4E6, Canada; Graduate Bioinformatics Training Program, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
5
Department of Molecular Oncology, BC Cancer, Vancouver, BC V5Z 4E6, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
6
Department of Statistics, University of Oxford, Oxford OX1 2JD, UK; Ludwig Institute for Cancer Research, University of Oxford, Oxford OX1 2JD, UK.
7
Department of Anatomical Pathology, Vancouver General Hospital, Vancouver, BC V5Z 1M9, Canada.
8
Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC V5Z 4E6, Canada.
9
Centre for Evolution and Cancer, The Institute of Cancer Research, London SM2 5NG, UK; Division of Molecular Pathology, The Institute of Cancer Research, London SM2 5NG, UK.
10
Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC V5Z 4E6, Canada; Genome Science and Technology Program, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
11
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
12
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Department of Gynecology and Obstetrics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
13
Department of Statistics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
14
BC Children's Hospital Research, Vancouver, BC V5Z 4H4, Canada.
15
Department of Gynecology and Obstetrics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
16
Deeley Research Centre, BC Cancer, Victoria, BC V8R 6V5, Canada; Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC V8P 3E6, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. Electronic address: bnelson@bccrc.ca.
17
Department of Molecular Oncology, BC Cancer, Vancouver, BC V5Z 4E6, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. Electronic address: sshah@bccrc.ca.

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.

KEYWORDS:

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

PMID:
29754820
DOI:
10.1016/j.cell.2018.03.073
[Indexed for MEDLINE]

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