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

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.