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Updated: Jun 25, 2026
Colorectal Cancer Cell Surface Protein Profiling Using an Antibody Microarray and Fluorescence Multiplexing
Published on: September 25, 2011
Single-Cell Multi-Tissue T Cell Clonal Dynamics Reveal Distinct Immune Coercion Landscapes in MSI and MSS Colorectal
Qianhe Zhan1,2, Siwen Zhang2,3, Bofu Cao2,4
1College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China.
Abstract:
The efficacy of immunotherapy in colorectal cancer (CRC) has long been considered to be closely associated with microsatellite instability (MSI) status. Patients with microsatellite stable (MSS) tumors typically exhibit poor responses to PD-1/PD-L1 inhibitors and a poor prognosis, often being categorized as immunologically 'cold' tumors. However, some MSS patients can still achieve favorable therapeutic responses, sometimes even surpassing those of certain MSI patients. Immune-cold and immune-hot tumor phenotypes are largely determined by the abundance, clonal expansion, and functional states of tumor-infiltrating T cells. This suggests that immunotherapy responses are driven by dynamic remodeling of T-cell clonality rather than by MSI status alone. To elucidate the underlying T cell clonal dynamics, integrated single-cell transcriptome (scRNA-seq) and T cell receptor sequencing (scTCR-seq) data analyses from 43 blood and tissue samples of MSI and MSS colorectal cancer patients before and after anti-PD-1 therapy were performed. Using our developed TCR reconstruction pipeline (TORBiT), we systematically analyzed the clonal architecture of the TCR repertoire, inter-tissue migration, and its association with T-cell functional state transitions. From a TCR clonal kinetic perspective, we revealed two distinct modes of immune Coercion that may further affect the immune response: a "high-fluctuation, deep-exhaustion" pattern in MSI tumors and a "high-baseline, strong-suppression" pattern in MSS tumors. These findings provide a novel theoretical foundation and research perspective for understanding the responsiveness and resistance mechanisms to immune checkpoint inhibitors.
Insights
Immunotherapy response in colorectal cancer (CRC) depends on T-cell dynamics, not just microsatellite instability (MSI) status. Analyzing T-cell receptor (TCR) repertoires revealed distinct immune coercion patterns in MSI and microsatellite stable (MSS) tumors.
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.
