Unraveling tumor-immune heterogeneity in advanced ovarian cancer uncovers immunogenic effect of chemotherapy
| Autor: | Jiménez-Sánchez, Alejandro, Cybulska, Paulina, Mager, Katherine LaVigne, Koplev, Simon, Cast, Oliver, Couturier, Dominique-Laurent, Memon, Danish, Selenica, Pier, Nikolovski, Ines, Mazaheri, Yousef, Bykov, Yonina, Geyer, Felipe C, Macintyre, Geoff, Gavarró, Lena Morrill, Drews, Ruben M, Gill, Michael B, Papanastasiou, Anastasios D, Sosa, Ramon E, Soslow, Robert A, Walther, Tyler, Shen, Ronglai, Chi, Dennis S, Park, Kay J, Hollmann, Travis, Reis-Filho, Jorge S, Markowetz, Florian, Beltrao, Pedro, Vargas, Hebert Alberto, Zamarin, Dmitriy, Brenton, James D, Snyder, Alexandra, Weigelt, Britta, Sala, Evis, Miller, Martin L |
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| Předmět: |
Ovarian Neoplasms
Principal Component Analysis DNA Copy Number Variations Gene Expression Profiling Genes myc chemical and pharmacologic phenomena 3. Good health Cystadenocarcinoma Serous Cohort Studies Gene Expression Regulation Neoplastic Killer Cells Natural Mice Lymphocytes Tumor-Infiltrating Mutation Tumor Microenvironment Animals Humans Female Cisplatin Wnt Signaling Pathway |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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