Low-dose albumin-bound paclitaxel and enhancement of anti-PD-1 therapy in bladder cancer by shaping the inflammatory immune microenvironment through induction of mitochondrial stress: Results from the phase 2 TRUCE-01 and TRUCE-02 trails.

Abstract

e16597 Background: Our previous studies demonstrated that low-dose albumin-bound paclitaxel combined with toripalimab achieved a complete clinical response (cCR) rate of 52% in muscle-invasive bladder cancer (MIBC) and 62.7% in non-muscle-invasive bladder cancer (NMIBC), based on findings from the Truce-01 and Truce-02 clinical trials. Methods: Tumor samples from patients enrolled in the Truce-01 and Truce-02 trials, collected before and after treatment, were analyzed using single-cell RNA sequencing (scRNA-seq) and multiplex immunofluorescence (mIHC) on formalin-fixed paraffin-embedded (FFPE) tissues to assess cytokine expression. Biomarker changes were further evaluated using immunohistochemistry (IHC), and quantitative analysis was performed using the Inform image analysis software. Correlations between sequencing biomarkers and cytokines were assessed using Pearson linear regression models, with a significance threshold set at 5%. Results: Comparative scRNA-seq analysis of pre- and post-treatment tumor tissues from three responding patients revealed significant changes in mitochondrial gene expression, characterized by elevated IFI27 expression. Validation in tissue samples from 181 patients confirmed a positive correlation between IFI27 expression and treatment response. Additionally, inflammatory cytokine analysis in these patients revealed significant upregulation of CXCL11, CCL2, IL6, TNF, and CXCL8, which also positively correlated with IFI27 expression levels. Conclusions: Our findings suggest that low-dose albumin-bound paclitaxel induces mitochondrial stress, represented by elevated IFI27 expression. IFI27 expression is positively correlated with the expression of multiple inflammatory cytokines and clinical outcomes, highlighting its potential role in enhancing the inflammatory immune microenvironment and improving the efficacy of anti-PD-1 therapy.