TY - JOUR
T1 - Unraveling tumor–immune heterogeneity in advanced ovarian cancer uncovers immunogenic effect of chemotherapy
AU - Jiménez-Sánchez, Alejandro
AU - Cybulska, Paulina
AU - Mager, Katherine La Vigne
AU - Koplev, Simon
AU - Cast, Oliver
AU - Couturier, Dominique Laurent
AU - Memon, Danish
AU - Selenica, Pier
AU - Nikolovski, Ines
AU - Mazaheri, Yousef
AU - Bykov, Yonina
AU - Geyer, Felipe C.
AU - Macintyre, Geoff
AU - Gavarró, Lena Morrill
AU - Drews, Ruben M.
AU - Gill, Michael B.
AU - Papanastasiou, Anastasios D.
AU - Sosa, Ramon E.
AU - Soslow, Robert A.
AU - Walther, Tyler
AU - Shen, Ronglai
AU - Chi, Dennis S.
AU - Park, Kay J.
AU - Hollmann, Travis
AU - Reis-Filho, Jorge S.
AU - Markowetz, Florian
AU - Beltrao, Pedro
AU - Vargas, Hebert Alberto
AU - Zamarin, Dmitriy
AU - Brenton, James D.
AU - Snyder, Alexandra
AU - Weigelt, Britta
AU - Sala, Evis
AU - Miller, Martin L.
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85085894884
U2 - 10.1038/s41588-020-0630-5
DO - 10.1038/s41588-020-0630-5
M3 - Article
C2 - 32483290
AN - SCOPUS:85085894884
SN - 1061-4036
VL - 52
SP - 582
EP - 593
JO - Nature Genetics
JF - Nature Genetics
IS - 6
ER -