Single-Cell Multi-Tissue T Cell Clonal Dynamics Reveal Distinct Immune Coercion Landscapes in MSI and MSS Colorectal...

Area of Science:

• Oncology
• Immunology
• Genomics

Background:

• Immunotherapy efficacy in colorectal cancer (CRC) is often linked to microsatellite instability (MSI) status.
• Microsatellite stable (MSS) tumors typically show poor response to PD-1/PD-L1 inhibitors, but some patients benefit, suggesting factors beyond MSI status influence outcomes.
• Tumor phenotypes (immune-cold vs. immune-hot) are determined by T-cell abundance, expansion, and function, indicating T-cell clonality drives immunotherapy response.

Purpose of the Study:

• To investigate the role of T-cell clonal dynamics in immunotherapy response in colorectal cancer.
• To analyze T-cell receptor (TCR) repertoire architecture, inter-tissue migration, and functional states in MSI and MSS CRC patients.
• To identify distinct immune coercion patterns associated with different tumor subtypes and their impact on anti-PD-1 therapy response.

Main Methods:

• Integrated single-cell transcriptome (scRNA-seq) and T-cell receptor sequencing (scTCR-seq) on 43 blood and tissue samples from MSI and MSS CRC patients.
• Utilized a developed TCR reconstruction pipeline (TORBiT) for systematic analysis of TCR repertoire clonal architecture.
• Examined inter-tissue migration and association with T-cell functional state transitions before and after anti-PD-1 therapy.

Main Results:

• Revealed two distinct modes of immune coercion influencing immunotherapy response: 'high-fluctuation, deep-exhaustion' in MSI tumors and 'high-baseline, strong-suppression' in MSS tumors.
• Demonstrated that T-cell clonal kinetics, rather than MSI status alone, are critical drivers of immunotherapy responsiveness.
• Identified specific TCR clonal dynamics associated with varying responses to anti-PD-1 therapy in colorectal cancer patients.

Conclusions:

• T-cell clonal dynamics play a crucial role in determining immunotherapy response in colorectal cancer, offering a new perspective beyond MSI status.
• The identified immune coercion patterns provide a novel theoretical framework for understanding immunotherapy resistance and responsiveness mechanisms.
• Findings suggest that targeting T-cell clonal kinetics could be a future strategy for optimizing immune checkpoint inhibitor therapy in CRC.