Transcriptomic Determinants of Response to Pembrolizumab Monotherapy across Solid Tumor Types

Area of Science:

• Immunogenomics
• Cancer Biology
• Pharmacogenomics

Background:

• Pembrolizumab efficacy is linked to T-cell inflamed gene expression profiles (TcellinfGEP).
• Understanding additional biological factors influencing response is crucial for optimizing immunotherapy.
• Tumor microenvironment and metabolic pathways may modulate anti-PD-1 therapy outcomes.

Purpose of the Study:

• To investigate the association between 11 biological gene expression signatures and response to pembrolizumab monotherapy.
• To identify novel biomarkers beyond T-cell inflammation that predict pembrolizumab efficacy.
• To explore relationships between gene expression patterns and objective response rate in diverse cancer types.

Main Methods:

• RNA-sequencing data from 1,188 patients across seven tumor types treated with pembrolizumab were analyzed.
• Eleven predefined gene expression signatures were evaluated for their correlation with objective response rate (RECIST v1.1).
• Logistic regression models adjusted for tumor type and performance status were used, with TcellinfGEP as a covariate.

Main Results:

• TcellinfGEP showed a positive association with pembrolizumab response.
• Signatures for angiogenesis, monocytic myeloid-derived suppressor cells (mMDSC), and stroma/epithelial-to-mesenchymal transition (EMT)/TGFβ were negatively associated with response.
• Concordant coexpression patterns were observed between TcellinfGEP and other signatures in independent datasets.

Conclusions:

• Gene expression signatures beyond T-cell inflammation are relevant to anti-PD-1 monotherapy response.
• Tumor biology features, including angiogenesis and immune suppressive cells, offer potential targets for combination therapies.
• These findings expand the understanding of mechanisms underlying pembrolizumab efficacy and resistance.