Mismatch Repair-Proficient Colorectal Cancer can evade Immune Surveillance Through an Intrinsic Suppressive Program.

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.