Peripheral CD8⁺ T cell characteristics associated with durable responses to immune checkpoint blockade in patients...

Area of Science:

• Immunology
• Oncology
• Genomics

Background:

• Metastatic melanoma (MM) treatment with immune checkpoint blockade (ICB) targeting PD-1 and CTLA-4 has inconsistent efficacy.
• Understanding peripheral CD8+ T cell responses is crucial for predicting ICB therapeutic benefit.

Purpose of the Study:

• To characterize CD8+ T cell gene expression and T cell receptor (TCR) clonality in MM patients undergoing ICB.
• To identify molecular and cellular markers associated with durable clinical benefit from ICB.

Main Methods:

• Gene expression profiling of CD8+ T cells from MM patients receiving anti-PD-1 (sICB) or combination anti-PD-1/anti-CTLA-4 (cICB).
• TCR clonality analysis and single-cell RNA-sequencing (scRNA-seq) of peripheral T cells.
• Correlation of molecular findings with clinical response at 6 months.

Main Results:

• Combination ICB (cICB) induced a greater magnitude of CD8+ T cell response than single-agent ICB (sICB), with increased mitosis and interferon-related gene expression.
• Patients with durable clinical benefit showed overexpression of TCR-encoding genes and a higher proportion of large TCR clones post-treatment.
• Large CD8+ T cell clones were enriched for cytotoxicity and effector memory markers (CCL4, GNLY, NKG7) and correlated with effector memory T cell percentage.
• A higher count of large CD8+ T cell clones at 21 days post-treatment predicted 6-month clinical response, irrespective of clonal specificity.

Conclusions:

• Peripheral CD8+ T cell transcriptional and clonal responses to ICB are dose-dependent and associated with treatment efficacy.
• Post-ICB CD8+ T cell clonality, specifically the expansion of large clones, serves as a predictive biomarker for long-term response in metastatic melanoma.
• Assessing peripheral CD8+ T cell clonality may aid in stratifying patients for ICB therapy.