循環トランスクリプトーム解析により、膀胱がんにおける免疫療法への反応を予測する遺伝子シグネチャーおよび免疫細胞の活性化と量が発見される

Immune Checkpoint Blockers (ICB) have revolutionized oncology by achieving durable tumor responses in advanced cancers. Nevertheless, currently approved biomarkers (PD-L1, MSI, TMB) have suboptimal positive and negative predictive values for tumor response and survival.

We aimed to assess the value of RNA sequencing from whole blood to predict responses to ICB. We performed total paired-end RNA sequencing at 20 million reads and analyzed differential gene expression, signaling pathway activation, and immune cell abundances according to cancer outcomes. The analysis was conducted on baseline frozen whole blood samples from 164 patients prospectively enrolled in the IOPREDI study.

We found that some immune-related genes and signaling pathways were highly expressed in patients who achieved a durable clinical benefit. Furthermore, analyses of both progression-free survival (PFS) and overall survival (OS) confirmed significantly higher expression levels of immune-related signaling pathways in long-term survivors. Gene expression signatures capable of classifying patients based on clinical response or PFS were also identified. Interestingly, deconvolution analysis revealed a significant higher abundance of resting NK cells in patients with prolonged PFS or OS, in contrast to other cytotoxic cell types. Finally, high expression of the CST7 gene and increased abundance of naïve B lymphocytes were associated with immune-related adverse events (irAEs).

Total RNA sequencing from whole blood provides high-quality data to predict clinical response, survival, and occurrence of irAEs. The use of this type of samples prior to immune checkpoint blockage could improve treatment efficacy and irAEs management.