Pan cohort immune biomarker of CD8 lymphocyte activation enabling HGSOC outcome prediction and treatment response.

BACKGROUND

High-grade serous ovarian cancer (HGSOC) exhibits poor prognosis due to late diagnosis, chemoresistance, and limited responses to immune checkpoint inhibitors. Although tumor-infiltrating CD8+ T cells correlate with improved survival, current prognostic models remain inadequate. Thus, robust biomarkers linked to CD8+ T cell activation are urgently needed to guide clinical management.

METHODS

Transcriptomic and clinical profiles from 874 late-stage HGSOC patients were analyzed via single-sample gene set enrichment analysis for immune infiltration and weighted gene co-expression network analysis to identify CD8+ T cell-associated genes. An integrative machine learning approach was employed to develop a CD8⁺ T cell-associated immune prognostic signature (CIPS), which was then validated across multiple independent cohorts and benchmarked against 56 published models. CIPS was further characterized using single-cell RNA-seq analysis.

RESULTS

The resulting 10-gene signature independently predicted overall survival in all cohorts and consistently surpassed most clinicopathological variables and comparator models. Low-risk patients exhibited significantly enhanced CD8+ T cell and cytotoxic gene scores, correlating with better responses to chemotherapy and immunotherapy. CIPS inversely correlated with tumor-mutation burden, BRCA1/2 mutations and homologous-recombination deficiency. Single-cell analysis localized signature genes to T lymphocyte and myeloid compartments and linked elevated CIPS activity to augmented intercellular communication in platinum-resistant tumors.

CONCLUSION

CIPS captures a CD8+ T cell activation program that powerfully stratifies late-stage HGSOC, forecasts therapeutic benefit and offers a practicable biomarker for personalized immuno-oncology strategies.