Unraveling tumor-immune heterogeneity in advanced ovarian cancer uncovers immunogenic effect of chemotherapy
Alejandro Jiménez-Sánchez, Paulina Cybulska, Katherine LaVigne Mager, Simon Koplev, Oliver Cast, Dominique-Laurent 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, Dennis S Chi, Kay J Park, Travis Hollmann, Jorge S Reis-Filho, Florian Markowetz, Pedro Beltrao, Hebert Alberto Vargas, Dmitriy Zamarin, James D Brenton, Alexandra Snyder, Britta Weigelt, Evis Sala, Martin L Miller, Alejandro Jiménez-Sánchez, Paulina Cybulska, Katherine LaVigne Mager, Simon Koplev, Oliver Cast, Dominique-Laurent 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, Dennis S Chi, Kay J Park, Travis Hollmann, Jorge S Reis-Filho, Florian Markowetz, Pedro Beltrao, Hebert Alberto Vargas, Dmitriy Zamarin, James D Brenton, Alexandra Snyder, Britta Weigelt, Evis Sala, Martin L Miller
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.
Conflict of interest statement
COMPETING INTERESTS
A.S. is a current employee of, and owns stock in, Merck. D.S.C. is on two medical advisory boards and invested in two surgical companies but none of those are related to this research. J.S.R.-F. is a paid consultant of Goldman Sachs Merchant Banking, Paige.AI and REPARE Therapeutics, and member of the scientific advisory board with paid honoraria of Paige.AI and Volition Rxand an ad-hoc member of the scientific advisory boards of Roche Tissue Diagnostics, Ventana, InVicro, Genentech, Novartis, GRAIL and Roche, outside the submitted work. D.Z. reports personal/consultancy fees from Merck, Synlogic Therapeutics, Biomed Valley Discoveries, Trieza Therapeutics, Tesaro and Agenus out of the scope of the submitted work. M.L.M. has received honoraria from GSK, but not related to this research. E.S. is a co-founder and shareholder of Cambridge AI Heath, consultant for Amazon and received honoraria from GSK, but none of these are related to this research. G.M. is founder and CTO of Pinpoint Oncology Ltd. A.J.-S. has owned and sold stocks while this work was in progress, none of which relates directly with this publication.
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Source: PubMed