Profiling Multiple CD8+ T-cell Functional Dimensions Enhances Breast Cancer Immune Assessment

Area of Science:

• Immunology
• Oncology
• Bioinformatics

Background:

• CD8+ T-cell abundance alone is inadequate for predicting breast cancer prognosis and immunotherapy response due to complex T-cell functions.
• Single-cell RNA sequencing (scRNA-seq) can detail T-cell functions but has limited clinical applicability.

Purpose of the Study:

• To develop and validate bulk RNA sequencing-based models (FuncDimen) to assess multifaceted CD8+ T-cell functionalities.
• To create an aggregated score (FuncAggre) for a comprehensive evaluation of antitumor immunity.
• To improve prognostic prediction and personalize immunotherapy for breast cancer patients.

Main Methods:

• Integrative analysis of scRNA-seq and matched bulk RNA sequencing (bulk RNA-seq) data to build FuncDimen models.
• Evaluation of five CD8+ T-cell functional dimensions: tumor reactivity, cytotoxicity, IFNγ secretion, proliferation, and apoptosis.
• Validation of FuncDimen models and calculation of FuncAggre score using breast cancer cohorts and external databases via immunofluorescence and imaging mass cytometry.

Main Results:

• FuncDimen models successfully quantified distinct CD8+ T-cell functions.
• The FuncAggre score demonstrated superior predictive performance for breast cancer prognosis (time-dependent AUC: 0.56-0.70) and immunotherapy response (AUC: 0.71-0.83) compared to other immune biomarkers.
• The FuncAggre score's predictive power was consistent across different breast cancer molecular subtypes.

Conclusions:

• FuncDimen models provide a refined, clinically applicable assessment of CD8+ T-cell-mediated antitumor immunity.
• The FuncAggre score enhances prognostic prediction and supports personalized immunotherapy strategies in breast cancer.
• This approach offers a more robust evaluation of immune status than traditional methods.