Synapse - Unraveling tumor–immune heterogeneity in advanced ovarian cancer uncovers immunogenic effect of chemotherapy

Unraveling tumor–immune heterogeneity in advanced ovarian cancer uncovers immunogenic effect of chemotherapy Journal Article

Authors:	Jiménez-Sánchez, A.; Cybulska, P.; LaVigne Mager, K.; Koplev, S.; Cast, O.; Couturier, D. L.; Memon, D.; Selenica, P.; Nikolovski, I.; Mazaheri, Y.; Bykov, Y.; Geyer, F. C.; Macintyre, G.; Gavarró, L. M.; Drews, R. M.; Gill, M. B.; Papanastasiou, A. D.; Sosa, R. E.; Soslow, R. A.; Walther, T.; Shen, R.; Chi, D. S.; Park, K. J.; Hollmann, T.; Reis-Filho, J. S.; Markowetz, F.; Beltrao, P.; Vargas, H. A.; Zamarin, D.; Brenton, J. D.; Snyder, A.; Weigelt, B.; Sala, E.; Miller, M. L.
Article Title:	Unraveling tumor–immune heterogeneity in advanced ovarian cancer uncovers immunogenic effect of chemotherapy
Abstract:	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. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
Keywords:	immunohistochemistry; adult; cancer chemotherapy; clinical article; controlled study; human tissue; aged; middle aged; gene mutation; cisplatin; advanced cancer; nonhuman; cancer staging; flow cytometry; nuclear magnetic resonance imaging; prospective study; cd8 antigen; transcription factor foxp3; t lymphocyte; mouse; animal tissue; ovary cancer; gene expression; cell infiltration; animal experiment; animal model; cohort analysis; genetic transcription; immunofluorescence; brca1 protein; brca2 protein; amino acid sequence; cd11b antigen; myc protein; natural killer cell; neoadjuvant chemotherapy; gene dosage; wnt protein; cell expansion; immunocompetent cell; cd19 antigen; helper cell; genetic heterogeneity; tumor microenvironment; wnt signaling; cell composition; tumor immunogenicity; three-dimensional imaging; dna sequencing; human; female; priority journal; article; whole exome sequencing; immune-related gene
Journal Title:	Nature Genetics
Volume:	52
Issue:	6
ISSN:	1061-4036
Publisher:	Nature Publishing Group
Date Published:	2020-06-01
Start Page:	582
End Page:	593
Language:	English
DOI:	10.1038/s41588-020-0630-5
PUBMED:	32483290
PROVIDER:	scopus
PMCID:	PMC8353209
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85085894884&doi=10.1038%2fs41588-020-0630-5&partnerID=40&md5=025fbbfb13855dd26708405a1667cb4e
Notes:	Article -- Export Date: 1 July 2020 -- Source: Scopus