T-cell priming transcriptomic markers: implications of immunome heterogeneity for precision immunotherapy

Area of Science:

• Oncology
• Immunology
• Genomics

Background:

• Immune checkpoint blockade (ICB) benefits only a subset of cancer patients.
• Targeting T-cell priming markers (TPMs) shows potential to improve ICB efficacy.
• Clinical application of TPMs is complex due to tumor immune heterogeneity.

Purpose of the Study:

• To analyze the expression of 15 TPMs across a pan-cancer cohort.
• To investigate correlations between TPM expression and key cancer biomarkers.
• To explore the potential of TPM immunomic profiles for optimizing cancer immunotherapy.

Main Methods:

• Transcriptomic analysis of 15 TPMs in 514 patients across 30 cancer types.
• Correlation analysis with histological type, microsatellite instability-high (MSI-H), tumor mutational burden (TMB), and PD-L1 expression.
• Hierarchical clustering to classify tumors into 'Hot', 'Mixed', or 'Cold' based on TPM expression.

Main Results:

• TPM expression showed no significant association with histological type.
• GZMB and IFNG expression were higher in tumors with MSI-H, high TMB (≥10 mutations/mb), and PD-L1 expression (≥1%).
• PD-L1 expression (≥1%) correlated with higher CD137, GITR, and ICOS expression. Tumors were classified into distinct immunomic clusters, with 'cold' clusters having less PD-L1 expression.

Conclusions:

• Diverse TPM expression patterns exist across cancers, independent of histology.
• TPM profiles correlate with established immunotherapy biomarkers (PD-L1, MSI-H, TMB).
• Individualized patient selection based on TPM immunomic profiles may enhance immunotherapy outcomes.