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

View ORCID ProfileAllen W. Zhang, Andrew McPherson, Katy Milne, David R. Kroeger, Phineas T. Hamilton, Alex Miranda, Tyler Funnell, Sonya Laan, Dawn R. Cochrane, Jamie L.P. Lim, Winnie Yang, Andrew Roth, Maia A. Smith, Camila de Souza, Julie Ho, Kane Tse, Thomas Zeng, Inna Shlafman, Michael R. Mayo, Richard Moore, Henrik Failmezger, Andreas Heindl, Yi Kan Wang, Ali Bashashati, Scott D. Brown, Daniel Lai, Adrian N. C. Wan, Cydney B. Nielsen, Alexandre Bouchard-Côté, Yinyin Yuan, Wyeth W. Wasserman, C. Blake Gilks, Anthony N. Karnezis, Samuel Aparicio, Jessica N. McAlpine, David G. Huntsman, Robert A. Holt, Brad H. Nelson, Sohrab P. Shah
doi: https://doi.org/10.1101/198101
Allen W. Zhang
1Department of Molecular Oncology
3BC Children’s Hospital Research, Vancouver, BC, V5Z 4H4, Canada
11Graduate Bioinformatics Training Program
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  • ORCID record for Allen W. Zhang
Andrew McPherson
1Department of Molecular Oncology
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Katy Milne
4Deeley Research Centre, BC Cancer Agency, Victoria, BC, V8R 6V5, Canada
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David R. Kroeger
4Deeley Research Centre, BC Cancer Agency, Victoria, BC, V8R 6V5, Canada
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Phineas T. Hamilton
4Deeley Research Centre, BC Cancer Agency, Victoria, BC, V8R 6V5, Canada
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Alex Miranda
4Deeley Research Centre, BC Cancer Agency, Victoria, BC, V8R 6V5, Canada
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Tyler Funnell
1Department of Molecular Oncology
11Graduate Bioinformatics Training Program
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Sonya Laan
4Deeley Research Centre, BC Cancer Agency, Victoria, BC, V8R 6V5, Canada
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Dawn R. Cochrane
1Department of Molecular Oncology
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Jamie L.P. Lim
1Department of Molecular Oncology
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Winnie Yang
1Department of Molecular Oncology
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Andrew Roth
6Department of Statistics
7Ludwig Institute for Cancer Research University of Oxford, Oxford, OX1 2JD, U.K.
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Maia A. Smith
1Department of Molecular Oncology
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Camila de Souza
1Department of Molecular Oncology
13Department of Statistics
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Julie Ho
8Department of Anatomical Pathology, Vancouver General Hospital, Vancouver, BC, V5Z 1M9, Canada
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Kane Tse
2Michael Smith Genome Sciences Centre BC Cancer Agency, Vancouver, BC, V5Z 4E6, Canada
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Thomas Zeng
2Michael Smith Genome Sciences Centre BC Cancer Agency, Vancouver, BC, V5Z 4E6, Canada
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Inna Shlafman
2Michael Smith Genome Sciences Centre BC Cancer Agency, Vancouver, BC, V5Z 4E6, Canada
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Michael R. Mayo
2Michael Smith Genome Sciences Centre BC Cancer Agency, Vancouver, BC, V5Z 4E6, Canada
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Richard Moore
2Michael Smith Genome Sciences Centre BC Cancer Agency, Vancouver, BC, V5Z 4E6, Canada
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Henrik Failmezger
9Centre for Evolution and Cancer
10Division of Molecular Pathology The Institute of Cancer Research, London, SM2 5NG, U.K
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Andreas Heindl
9Centre for Evolution and Cancer
10Division of Molecular Pathology The Institute of Cancer Research, London, SM2 5NG, U.K
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Yi Kan Wang
1Department of Molecular Oncology
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Ali Bashashati
1Department of Molecular Oncology
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Scott D. Brown
2Michael Smith Genome Sciences Centre BC Cancer Agency, Vancouver, BC, V5Z 4E6, Canada
12Genome Science and Technology Program
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Daniel Lai
1Department of Molecular Oncology
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Adrian N. C. Wan
1Department of Molecular Oncology
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Cydney B. Nielsen
14Department of Pathology and Laboratory Medicine
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Alexandre Bouchard-Côté
13Department of Statistics
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Yinyin Yuan
9Centre for Evolution and Cancer
10Division of Molecular Pathology The Institute of Cancer Research, London, SM2 5NG, U.K
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Wyeth W. Wasserman
3BC Children’s Hospital Research, Vancouver, BC, V5Z 4H4, Canada
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C. Blake Gilks
14Department of Pathology and Laboratory Medicine
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Anthony N. Karnezis
14Department of Pathology and Laboratory Medicine
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Samuel Aparicio
1Department of Molecular Oncology
14Department of Pathology and Laboratory Medicine
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Jessica N. McAlpine
15Department of Gynecology and Obstetrics
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David G. Huntsman
1Department of Molecular Oncology
14Department of Pathology and Laboratory Medicine
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Robert A. Holt
2Michael Smith Genome Sciences Centre BC Cancer Agency, Vancouver, BC, V5Z 4E6, Canada
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Brad H. Nelson
4Deeley Research Centre, BC Cancer Agency, Victoria, BC, V8R 6V5, Canada
5Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, V8P 3E6, Canada
16Department of Medical Genetics University of British Columbia, Vancouver, BC, V6T 1Z3, Canada
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  • For correspondence: bnelson@bccrc.ca sshah@bccrc.ca
Sohrab P. Shah
1Department of Molecular Oncology
14Department of Pathology and Laboratory Medicine
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  • For correspondence: bnelson@bccrc.ca sshah@bccrc.ca
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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.

Footnotes

  • Lead contact: S.P.S.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 04, 2017.
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The interface of malignant and immunologic clonal dynamics in high-grade serous ovarian cancer
Allen W. Zhang, Andrew McPherson, Katy Milne, David R. Kroeger, Phineas T. Hamilton, Alex Miranda, Tyler Funnell, Sonya Laan, Dawn R. Cochrane, Jamie L.P. Lim, Winnie Yang, Andrew Roth, Maia A. Smith, Camila de Souza, Julie Ho, Kane Tse, Thomas Zeng, Inna Shlafman, Michael R. Mayo, Richard Moore, Henrik Failmezger, Andreas Heindl, Yi Kan Wang, Ali Bashashati, Scott D. Brown, Daniel Lai, Adrian N. C. Wan, Cydney B. Nielsen, Alexandre Bouchard-Côté, Yinyin Yuan, Wyeth W. Wasserman, C. Blake Gilks, Anthony N. Karnezis, Samuel Aparicio, Jessica N. McAlpine, David G. Huntsman, Robert A. Holt, Brad H. Nelson, Sohrab P. Shah
bioRxiv 198101; doi: https://doi.org/10.1101/198101
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The interface of malignant and immunologic clonal dynamics in high-grade serous ovarian cancer
Allen W. Zhang, Andrew McPherson, Katy Milne, David R. Kroeger, Phineas T. Hamilton, Alex Miranda, Tyler Funnell, Sonya Laan, Dawn R. Cochrane, Jamie L.P. Lim, Winnie Yang, Andrew Roth, Maia A. Smith, Camila de Souza, Julie Ho, Kane Tse, Thomas Zeng, Inna Shlafman, Michael R. Mayo, Richard Moore, Henrik Failmezger, Andreas Heindl, Yi Kan Wang, Ali Bashashati, Scott D. Brown, Daniel Lai, Adrian N. C. Wan, Cydney B. Nielsen, Alexandre Bouchard-Côté, Yinyin Yuan, Wyeth W. Wasserman, C. Blake Gilks, Anthony N. Karnezis, Samuel Aparicio, Jessica N. McAlpine, David G. Huntsman, Robert A. Holt, Brad H. Nelson, Sohrab P. Shah
bioRxiv 198101; doi: https://doi.org/10.1101/198101

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