License to kill: microsatellite instability and immune contexture

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Colorectal cancers (CRCs) with microsatellite instability (MSI), caused by DNA mismatch repair defects, exhibit a distinct tumor microenvironment with more cytotoxic CD8 T-cells (CTLs) and better prognosis than microsatellite-stable (MSS) CRCs.
• The precise mechanisms linking MMR deficiency to immune cell infiltration and patient survival remained unclear.

Purpose of the Study:

• To comprehensively analyze MSI colorectal tumors and understand the relationship between MSI, tumor-infiltrating immune cells, and patient prognosis.
• To evaluate the predictive power of the Immunoscore assay for CRC prognosis and immunotherapy response.

Main Methods:

• Comprehensive analysis of MSI colorectal tumors.
• Quantification of tumor-infiltrating T-cells using a standardized Immunoscore assay.
• Multivariate analyses to compare the prognostic value of Immunoscore and MSI.

Main Results:

• A positive correlation was found between frame-shift mutations (potential neo-epitopes) and CD8 T-cell density in MSI CRCs.
• MSI patients demonstrated naturally occurring CTLs targeting frame-shift mutation-derived antigens, suggesting active immunosurveillance and immunoediting.
• Multivariate analyses indicated that the Immunoscore significantly outperformed MSI in predicting recurrence and survival.

Conclusions:

• The prognostic value of MSI in colorectal cancer may stem from underlying differences in immune cell infiltration.
• The Immunoscore assay shows potential as a tool for predicting colorectal tumor prognosis and response to immunotherapies.