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 | |
| State | Published - Jun 14 2018 |
| Externally published | Yes |
Fingerprint
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)
Cite this
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
}
TY - JOUR
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.
PY - 2018/6/14
Y1 - 2018/6/14
N2 - 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.
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
UR - http://www.scopus.com/inward/record.url?scp=85046665554&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85046665554&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2018.03.073
DO - 10.1016/j.cell.2018.03.073
M3 - Article
C2 - 29754820
AN - SCOPUS:85046665554
VL - 173
SP - 1755-1769.e22
JO - Cell
JF - Cell
SN - 0092-8674
IS - 7
ER -