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 Shlafman; Michael 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

doi:10.1016/j.cell.2018.03.073

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 journal › Article › peer-review

69 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 language	English (US)
Pages (from-to)	1755-1769.e22
Journal	Cell
Volume	173
Issue number	7
DOIs	https://doi.org/10.1016/j.cell.2018.03.073
State	Published - Jun 14 2018
Externally published	Yes

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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10.1016/j.cell.2018.03.073

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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

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

In: Cell, Vol. 173, No. 7, 14.06.2018, p. 1755-1769.e22.

Research output: Contribution to journal › Article › peer-review

Zhang, AW, McPherson, A, Milne, K, Kroeger, DR, Hamilton, PT, Miranda, A, Funnell, T, Little, N, de Souza, CPE, Laan, S, LeDoux, S, Cochrane, DR, Lim, JLP, Yang, W, Roth, A, Smith, MA, Ho, J, Tse, K, Zeng, T, Shlafman, I, Mayo, MR, Moore, R, Failmezger, H, Heindl, A, Wang, YK, Bashashati, A, Grewal, DS, Brown, SD, Lai, D, Wan, ANC, Nielsen, CB, Huebner, C, Tessier-Cloutier, B, Anglesio, MS, Bouchard-Côté, A, Yuan, Y, Wasserman, WW, Gilks, CB, Karnezis, A, Aparicio, S, McAlpine, JN, Huntsman, DG, Holt, RA, Nelson, BH & Shah, SP 2018, 'Interfaces of Malignant and Immunologic Clonal Dynamics in Ovarian Cancer', Cell, vol. 173, no. 7, pp. 1755-1769.e22. https://doi.org/10.1016/j.cell.2018.03.073

Zhang, Allen W. ; McPherson, Andrew ; Milne, Katy ; Kroeger, David R. ; Hamilton, Phineas T. ; Miranda, Alex ; Funnell, Tyler ; Little, Nicole ; de Souza, Camila P.E. ; Laan, Sonya ; LeDoux, Stacey ; Cochrane, Dawn R. ; Lim, Jamie L.P. ; Yang, Winnie ; Roth, Andrew ; Smith, Maia A. ; Ho, Julie ; Tse, Kane ; Zeng, Thomas ; Shlafman, Inna ; Mayo, Michael R. ; Moore, Richard ; Failmezger, Henrik ; Heindl, Andreas ; Wang, Yi Kan ; Bashashati, Ali ; Grewal, Diljot S. ; Brown, Scott D. ; Lai, Daniel ; Wan, Adrian N.C. ; Nielsen, Cydney B. ; Huebner, Curtis ; Tessier-Cloutier, Basile ; Anglesio, Michael S. ; Bouchard-Côté, Alexandre ; Yuan, Yinyin ; Wasserman, Wyeth W. ; Gilks, C. Blake ; Karnezis, Anthony ; Aparicio, Samuel ; McAlpine, Jessica N. ; Huntsman, David G. ; Holt, Robert A. ; Nelson, Brad H. ; Shah, Sohrab P. / Interfaces of Malignant and Immunologic Clonal Dynamics in Ovarian Cancer. In: Cell. 2018 ; Vol. 173, No. 7. pp. 1755-1769.e22.

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title = "Interfaces of Malignant and Immunologic Clonal Dynamics in Ovarian Cancer",

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.",

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",

author = "Zhang, {Allen W.} and Andrew McPherson and Katy Milne and Kroeger, {David R.} and Hamilton, {Phineas T.} and Alex Miranda and Tyler Funnell and Nicole Little and {de Souza}, {Camila P.E.} and Sonya Laan and Stacey LeDoux and Cochrane, {Dawn R.} and Lim, {Jamie L.P.} and Winnie Yang and Andrew Roth and Smith, {Maia A.} and Julie Ho and Kane Tse and Thomas Zeng and Inna Shlafman and Mayo, {Michael R.} and Richard Moore and Henrik Failmezger and Andreas Heindl and Wang, {Yi Kan} and Ali Bashashati and Grewal, {Diljot S.} and Brown, {Scott D.} and Daniel Lai and Wan, {Adrian N.C.} and Nielsen, {Cydney B.} and Curtis Huebner and Basile Tessier-Cloutier and Anglesio, {Michael S.} and Alexandre Bouchard-C{\^o}t{\'e} and Yinyin Yuan and Wasserman, {Wyeth W.} and Gilks, {C. Blake} and Anthony Karnezis and Samuel Aparicio and McAlpine, {Jessica N.} and Huntsman, {David G.} and Holt, {Robert A.} and Nelson, {Brad H.} and Shah, {Sohrab P.}",

year = "2018",

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T1 - Interfaces of Malignant and Immunologic Clonal Dynamics in Ovarian Cancer

AU - Zhang, Allen W.

AU - McPherson, Andrew

AU - Milne, Katy

AU - Kroeger, David R.

AU - Hamilton, Phineas T.

AU - Miranda, Alex

AU - Funnell, Tyler

AU - Little, Nicole

AU - de Souza, Camila P.E.

AU - Laan, Sonya

AU - LeDoux, Stacey

AU - Cochrane, Dawn R.

AU - Lim, Jamie L.P.

AU - Yang, Winnie

AU - Roth, Andrew

AU - Smith, Maia A.

AU - Ho, Julie

AU - Tse, Kane

AU - Zeng, Thomas

AU - Shlafman, Inna

AU - Mayo, Michael R.

AU - Moore, Richard

AU - Failmezger, Henrik

AU - Heindl, Andreas

AU - Wang, Yi Kan

AU - Bashashati, Ali

AU - Grewal, Diljot S.

AU - Brown, Scott D.

AU - Lai, Daniel

AU - Wan, Adrian N.C.

AU - Nielsen, Cydney B.

AU - Huebner, Curtis

AU - Tessier-Cloutier, Basile

AU - Anglesio, Michael S.

AU - Bouchard-Côté, Alexandre

AU - Yuan, Yinyin

AU - Wasserman, Wyeth W.

AU - Gilks, C. Blake

AU - Karnezis, Anthony

AU - Aparicio, Samuel

AU - McAlpine, Jessica N.

AU - Huntsman, David G.

AU - Holt, Robert A.

AU - Nelson, Brad H.

AU - Shah, Sohrab P.

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AB - 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.

KW - clonal evolution

KW - clone

KW - foldback inversion

KW - HGSC

KW - high-grade serous ovarian cancer

KW - HLA

KW - human leukocyte antigen

KW - immunoediting

KW - intratumoral heterogeneity

KW - metastatic

KW - mutation signature

KW - tumor-infiltrating lymphocyte

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