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[Expression of the cGAS-STING Pathway in dMMR/MSI-H in Colorectal Cancer]
Akinao Kaneta1, Shotaro Nakajima, Kosaku Mimura
1Dept. of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine.
Abstract:
Deficient mismatch repair (dMMR)/microsatellite instability (MSI)-H colorectal cancer (CRC) has high immunogenicity. Although the cyclic GMP-AMP synthase( cGAS)-stimulator of interferon genes( STING) pathway activation has considerably contributed to the high number of CD8+ tumor-infiltrating lymphocytes (TILs), its role in dMMR/MSI-H CRC is largely unknown. In this study, we investigated the association between cGAS-STING expression and CD8+ TILs in CRC. Data analysis using the TCGA dataset CRC cohort showed that cGAS, STING, and CD8 gene expression levels were significantly higher in the MSI group. Immunohistochemistry examination of resected clinical CRC samples showed that cGAS-STING expression in tumor cells was high in the MSI CRC, and CD8+ TILs was also significantly infiltrated in the MSI group. Moreover, significant CD8+ TILs infiltration was observed in CRC with high cGAS and STING expression levels. The results suggest that dMMR/MSI -H CRC has maintained a high cGAS-STING expression, which may contribute to abundant CD8+ TILs.
Insights
Deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer (CRC) shows elevated cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway expression. This pathway activation is linked to increased CD8+ tumor-infiltrating lymphocytes (TILs) in CRC.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Context:
- Deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer (CRC) exhibits high immunogenicity.
- The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is known to influence CD8+ tumor-infiltrating lymphocytes (TILs).
- The specific role of the cGAS-STING pathway in dMMR/MSI-H CRC remains largely unelucidated.
Purpose:
- To investigate the association between cGAS-STING pathway expression and CD8+ TILs infiltration in colorectal cancer.
- To determine if cGAS-STING expression is altered in dMMR/MSI-H CRC compared to other CRC subtypes.
- To explore the potential contribution of the cGAS-STING pathway to the immune microenvironment of dMMR/MSI-H CRC.
Summary:
- Analysis of The Cancer Genome Atlas (TCGA) CRC cohort revealed significantly higher gene expression of cGAS, STING, and CD8 in the MSI group.
- Immunohistochemistry on clinical CRC samples confirmed high cGAS-STING expression in tumor cells and significant CD8+ TIL infiltration in MSI CRC.
- CRC samples with high cGAS and STING expression demonstrated substantial CD8+ TIL infiltration, suggesting a link between pathway activation and immune cell presence.
Impact:
- The findings suggest that dMMR/MSI-H CRC maintains high cGAS-STING expression.
- This sustained pathway activation may be a key mechanism contributing to the abundant infiltration of CD8+ TILs in this cancer subtype.
- Understanding this relationship could inform novel immunotherapeutic strategies for dMMR/MSI-H colorectal cancer.
