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Molecular Diagnostics

Integrated immuno-transcriptomic analysis of ovarian cancer identifies a four-chemokine-dominated subtype with antitumor immune-active phenotype and favorable prognosis

British Journal of Cancer volume 131, pages 1068–1079 (2024)Cite this article

Subjects

Abstract

Background

Ovarian cancer (OV) is a heterogeneous disease but has traditionally been treated as an immunologically cold malignancy. The relationship between the immune-active cancer phenotype typified by a T helper 1 (Th-1) immune response and clinical outcome in OV remains uncertain.

Methods

A cohort-scale compendium of transcriptomic data from 2850 OV samples from 19 individual datasets was compiled for integrative immuno-transcriptomic analysis. The immunological constant of rejection was used as a metric to assess the Th-1/cytotoxic response orientation and investigate the clinical-biological significance of immune polarization towards a Th-1 immune response. Single-cell RNA sequencing data from 39 OV samples were analyzed to elucidate the variability of the immune microenvironment, and immunohistochemical validation was performed on 39 samples from the Harbin Medical University Cancer Hospital.

Results

Our results demonstrated the prognostic significance of a Th-1/cytotoxic immune profile within the tumor microenvironment (TME) using the immunological constant of rejection classification to OV samples. Specifically, patients with tumors expressing high levels of ICR markers showed significantly improved survival. A gene panel consisting of four chemokines (CXCL9, CXCL10, CXCL11 and CXCL13) was identified as critical players in mediating the establishment of an active T-cell-inflamed antitumor phenotype. This 4-chemokine signature, which was extensively validated in external multicenter cohorts through transcriptomic profiling and in an independent in-house cohort through immunohistochemistry, introduced a novel immune classification in OV and identified a chemokine-dominated subtype associated with an active antitumor immune phenotype and favorable prognosis. Single-cell transcriptomic analysis revealed that chemokine-dominated tumors increase CXCR3 + NK and T cell recruitment to the TME primarily through the overexpression of macrophage-derived CXCL9/10/11.

Conclusions

This study provides new insights into understanding immune heterogeneity within the TME and paves the way for tailoring appropriate therapeutic interventions for patients with differing immune profiles.

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Fig. 1: Association of ICR-based immunological classification with clinical outcomes.
Fig. 2: Genomic and transcriptomic characterization of ICR-based immunological classification.
Fig. 3: Identification of a novel 4-chemokine-dominant molecular subtype.
Fig. 4: Expression of the 4-chemokine panel was associated with an active immune phenotype revealed by scRNA-Seq analysis.
Fig. 5: External validation of the novel 4-chemokines-dominant molecular subtype in different public cohorts.
Fig. 6: Immunostaining analyses and validation of the chemokines-dominant subtype in the HMUCH cohort.

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Data availability

The clinical and transcriptome data of ovarian tumors were retrieved from the GEO, TCGA and ArrayExpress data repositories. Single-cell RNA sequencing data were derived from Zheng’s study. Detailed information of ovarian cancer datasets used in this study in Supplementary Table 1.

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Funding

This study was supported by the National Natural Science Foundation of China (Grant No. 62272346), the Science and Technology Innovation Medical Development Foundation Project of Beijing (Grant No. KC2021-JF-0055-01), and the Medical Award Foundation Project of Beijing (Grant No. YXJL-2021-0577-0421, YXJL-2023-0894-0044). The funders had no roles in study design, data collection and analysis, publication decision, or manuscript preparation.

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Author notes

  1. These authors contributed equally: Lili Zhuo, Fanling Meng

Authors and Affiliations

  1. School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China

    Lili Zhuo, Meng Zhou & Jie Sun

  2. Department of Gynecology, Harbin Medical University Cancer Hospital, Harbin, 150081, China

    Fanling Meng & Kaidi Sun

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Contributions

MZ and JS conceived and designed the study. FLM and KDS prepared samples and performed the experiments. LLZ and FLM analyzed the data and interpreted the results. All authors were involved in writing the paper and had final approval of the submitted and published version.

Corresponding authors

Correspondence to Meng Zhou or Jie Sun.

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The study was performed in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of the Harbin Medical University Cancer Hospital (KY2021-45). Informed consent of patients was waived due to the retrospective nature of the study.

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Zhuo, L., Meng, F., Sun, K. et al. Integrated immuno-transcriptomic analysis of ovarian cancer identifies a four-chemokine-dominated subtype with antitumor immune-active phenotype and favorable prognosis. Br J Cancer 131, 1068–1079 (2024). https://doi.org/10.1038/s41416-024-02803-7

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