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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Pharmacology of Anti-Cancer Drugs
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1450751

Integrated analysis of single-cell and bulk transcriptome reveals hypoxia-induced immunosuppressive microenvironment to predict immunotherapy response in high-grade serous ovarian cancer

Provisionally accepted
Qingshan Chen Qingshan Chen 1Yue Zhang Yue Zhang 1Chao Wang Chao Wang 1Hui Ding Hui Ding 1Liqun Chi Liqun Chi 2*
  • 1 Shanghai First Maternity and Infant Hospital, Shanghai, Shanghai Municipality, China
  • 2 Haidian Maternal and Child Health Hospital of Beijing, Beijing, China

The final, formatted version of the article will be published soon.

    Background: Hypoxia is significantly associated with cancer progression and treatment outcomes. Nevertheless, the precise molecular mechanisms underlying the hypoxia-induced immunosuppressive microenvironment in high-grade serous ovarian cancer (HGSOC) are still not fully understood. Methods: By analyzing 5 independent transcriptomic datasets, we investigated the effect of hypoxia on prognosis and tumor microenvironment (TME) in HGSOC. The hypoxia levels and the intercellular communication signaling pathways were studied by using single-cell analysis. Furthermore, the Hypoxia-TME classifier was developed and then validated in the multiple HGSOC datasets. In addition, we also investigated the prognostic significance, genetic variations, signaling pathways, and the potential for immunotherapy benefits in different Hypoxia-TME subgroups.Results: Hypoxia was identified as a crucial risk factor in HGSOC, and strongly correlated with an immunosuppressive microenvironment characterized by alterations in the composition and distribution of immune cells. Single-cell analysis elucidated the heterogeneity inherent within the TME in HGSOC, and demonstrated an association between the hypoxic TME and fibroblasts as well as macrophages. CellChat analysis identified SPP1-CD44 and CXCL12-CXCR4 as the principal signaling axes through which macrophages and fibroblasts interact with T cells, respectively. Moreover, a personalized Hypoxia-TME classifier was constructed and validated through the integration of the hypoxia (18 genes) and TME (7 immune cells) scores. It was observed that patients in the Hypoxia low /TME high subgroup displayed a significantly better prognosis than other subgroups. Different subgroups exhibited unique genomic alterations and variations in signaling pathway differences, including TGF-β and Wnt/β-catenin pathways, which are closely associated with various biological functions. Finally, our results indicated that patients in the Hypoxia low /TME high subgroup exhibit a better response to immunotherapy, suggesting the potential utility of the Hypoxia-TME classifier as a new biomarker in HGSOC.Our study revealed hypoxia-induced immunosuppressive microenvironment, and developed Hypoxia-TME classifier to distinguish the prognosis, immune characteristics, and potential benefits of immunotherapy in HGSOC.

    Keywords: high-grade serous ovarian cancer, hypoxia, Immunotherapy, Immunosuppressive microenvironment, Single-Cell Analysis

    Received: 18 Jun 2024; Accepted: 28 Oct 2024.

    Copyright: © 2024 Chen, Zhang, Wang, Ding and Chi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Liqun Chi, Haidian Maternal and Child Health Hospital of Beijing, Beijing, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.