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Updated: May 14, 2026
Deficient Pms2, ERCC1, Ku86, CcOI in Field Defects During Progression to Colon Cancer
Published on: July 28, 2010
Mismatch Repair-Proficient Colorectal Cancer can evade Immune Surveillance Through an Intrinsic Suppressive Program
Chiara Maria Cattaneo1, Sharon Scardellato2, Gianluca Mauri3
1IRCCS Humanitas Research Hospital Milano Italy.
Abstract:
While microsatellite-instable (MSI) colorectal cancers (CRC), reflecting mismatch repair deficiency, often respond to immune checkpoint inhibitors, microsatellite-stable (MSS) tumors remain largely resistant. This disparity is typically attributed to differences in neoantigen load. However, whether antigen-independent mechanisms contribute to immune evasion in MSS-CRC remains unclear. To address this, we engineered a model in which MSI- and MSS-CRC cells express identical levels of a defined antigen recognized by TCR-engineered T cells. Despite equivalent antigen presentation, MSS tumors exhibited impaired T-cell activation, reduced cytotoxicity, and resistance to killing. We linked this immune evasion to the MSS tumor secretome, which suppressed immune responses even in immunogenic MSI cells by impairing immune synapse formation. Surfaceome profiling by mass spectrometry identified glycosylation-dependent alterations that impair immune recognition. Our findings demonstrate that MSS-CRC evades immune attack via intrinsic secretome-driven mechanisms, independent of antigenicity. Targeting glycosylation-linked suppressive pathways may restore T-cell responsiveness and improve immunotherapy efficacy in MSS-CRC.
Insights
Microsatellite-stable colorectal cancer (MSS-CRC) resists immunotherapy due to immune-suppressing factors in its secretions, not just low antigen levels. Targeting these factors, like altered glycosylation, could improve treatment effectiveness.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Microsatellite-instable (MSI) colorectal cancers (CRC) respond to immunotherapy, unlike microsatellite-stable (MSS) CRC.
- This difference is often linked to neoantigen load, but antigen-independent immune evasion in MSS-CRC is not well understood.
Purpose of the Study:
- To investigate antigen-independent immune evasion mechanisms in MSS-CRC.
- To determine if the tumor secretome contributes to immune evasion in MSS-CRC.
Main Methods:
- Engineered MSI- and MSS-CRC models with identical antigen presentation.
- Assessed T-cell activation, cytotoxicity, and killing resistance.
- Analyzed tumor secretome for immune-suppressive factors.
- Performed surfaceome profiling using mass spectrometry to identify glycosylation alterations.
Main Results:
- MSS-CRC tumors showed impaired T-cell activation and cytotoxicity despite equivalent antigen presentation.
- The MSS-CRC secretome suppressed immune responses by hindering immune synapse formation.
- Glycosylation-dependent alterations in the surfaceome were identified, impairing immune recognition.
Conclusions:
- MSS-CRC employs intrinsic, secretome-driven mechanisms for immune evasion, independent of antigenicity.
- Targeting glycosylation-linked suppressive pathways may enhance T-cell responsiveness and immunotherapy efficacy in MSS-CRC.
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