Open AccessUnraveling tumor–immune heterogeneity in advanced ovarian cancer uncovers immunogenic effect of chemotherapy
Author(s) -
Alejandro Jiménez-Sánchez,
Paulina Cybulska,
Katherine LaVigne Mager,
Simon Koplev,
Oliver Cast,
DominiqueLaurent Couturier,
Danish Memon,
Pier Selenica,
Ines Nikolovski,
Yousef Mazaheri,
Yonina Bykov,
Felipe C. Geyer,
Geoff Macintyre,
Lena Morrill Gavarró,
Ruben M. Drews,
Michael B. Gill,
Anastasios D. Papanastasiou,
Ramon E. Sosa,
Robert A. Soslow,
Tyler Walther,
Ronglai Shen,
S. Dennis,
Kay J. Park,
Travis J. Hollmann,
Jorge S. ReisFilho,
Florian Markowetz,
Pedro Beltrão,
Hebert Alberto Vargas,
Dmitriy Zamarin,
James D. Brenton,
Alexandra Snyder,
Britta Weigelt,
Evis Sala,
Martin L. Miller
Publication year - 2020
Publication title -
nature genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 18.861
H-Index - 573
eISSN - 1546-1718
pISSN - 1061-4036
DOI - 10.1038/s41588-020-0630-5
Subject(s) - immune system , biology , tumor microenvironment , ovarian cancer , cancer research , chemotherapy , immunotherapy , immunology , wnt signaling pathway , cancer , gene , genetics
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.