Tumor Infiltrating Lymphocytes and Macrophages Improve Survival in Microsatellite Unstable Colorectal Cancer

Area of Science:

• Oncology
• Genetics
• Immunology

Background:

• Colorectal cancer (CRC) with microsatellite instability (MSI) exhibits DNA repair deficiencies, leading to increased somatic mutations.
• These mutations may enhance tumor immunogenicity, potentially improving patient survival.
• Microsatellite instability-High (MSI-H) is a distinct molecular subtype of CRC.

Purpose of the Study:

• To investigate the association between MSI status and tumor immunogenicity in CRC.
• To explore the relationship between DNA repair gene expression, immune cell infiltration, and patient survival in MSI-H CRC.
• To identify potential therapeutic targets based on immune profiles of MSI-H tumors.

Main Methods:

• Utilized The Cancer Genome Atlas (TCGA) dataset for 283 CRC patients, comparing MSI-H and microsatellite stable (MSS) groups.
• Employed the CIBERSORT algorithm to estimate immune cell fractions within tumors.
• Analyzed gene expression data for DNA repair genes and immune checkpoint molecules.

Main Results:

• Low expression of DNA repair genes (MLH1, MLH3, PMS1, PMS2, ATR, PRKDC, ATM, BRCA2) was associated with MSI-H.
• MSI-H tumors showed increased infiltration of Helper T-cells and M1 macrophages.
• MSI-H tumors exhibited diminished intra-tumoral heterogeneity and higher expression of PD-1, PD-L1, CTLA4, LAG3, and TIM3.

Conclusions:

• Decreased DNA repair gene expression in MSI-H CRC correlates with increased tumor immunogenicity and favorable survival outcomes.
• Higher infiltration of tumor-infiltrating lymphocytes (TILs) and M1 macrophages, along with reduced heterogeneity, contributes to improved survival in MSI-H patients.
• The expression of immune checkpoint molecules in MSI-H tumors suggests potential for novel therapeutic strategies.