Unraveling tumor-immune heterogeneity in advanced ovarian cancer uncovers immunogenic effect of chemotherapy.
Animals
Cisplatin
/ immunology
Cohort Studies
Cystadenocarcinoma, Serous
/ drug therapy
DNA Copy Number Variations
Female
Gene Expression Profiling
/ statistics & numerical data
Gene Expression Regulation, Neoplastic
/ drug effects
Genes, myc
Humans
Killer Cells, Natural
/ drug effects
Lymphocytes, Tumor-Infiltrating
/ immunology
Mice
Mutation
Ovarian Neoplasms
/ drug therapy
Principal Component Analysis
Tumor Microenvironment
/ drug effects
Wnt Signaling Pathway
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
01
10
2018
accepted:
20
04
2020
pubmed:
3
6
2020
medline:
2
9
2020
entrez:
3
6
2020
Statut:
ppublish
Résumé
In metastatic cancer, the degree of heterogeneity of the tumor microenvironment (TME) and its molecular underpinnings remain largely unstudied. To characterize the tumor-immune interface at baseline and during neoadjuvant chemotherapy (NACT) in high-grade serous ovarian cancer (HGSOC), we performed immunogenomic analysis of treatment-naive and paired samples from before and after treatment with chemotherapy. In treatment-naive HGSOC, we found that immune-cell-excluded and inflammatory microenvironments coexist within the same individuals and within the same tumor sites, indicating ubiquitous variability in immune cell infiltration. Analysis of TME cell composition, DNA copy number, mutations and gene expression showed that immune cell exclusion was associated with amplification of Myc target genes and increased expression of canonical Wnt signaling in treatment-naive HGSOC. Following NACT, increased natural killer (NK) cell infiltration and oligoclonal expansion of T cells were detected. We demonstrate that the tumor-immune microenvironment of advanced HGSOC is intrinsically heterogeneous and that chemotherapy induces local immune activation, suggesting that chemotherapy can potentiate the immunogenicity of immune-excluded HGSOC tumors.
Identifiants
pubmed: 32483290
doi: 10.1038/s41588-020-0630-5
pii: 10.1038/s41588-020-0630-5
pmc: PMC8353209
mid: NIHMS1717099
doi:
Substances chimiques
Cisplatin
Q20Q21Q62J
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
582-593Subventions
Organisme : Cancer Research UK
ID : A19274
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C9685/A25177
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A15973
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A22905
Pays : United Kingdom
Organisme : Cancer Research UK
ID : 15601
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : Cancer Research UK
ID : C14303/A17197
Pays : United Kingdom
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