Impact of RAS/BRAFV600E Mutations on the Tumor Immune Microenvironment in Mismatch Repair-Deficient/Microsatellite...

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Mismatch repair deficient colorectal cancer (dMMR CRC) requires routine testing for Lynch Syndrome screening, prognosis, and treatment.
• RAS and BRAF mutations are critical for treatment decisions in metastatic CRC.
• The impact of RAS/BRAF mutations on the tumor immune microenvironment (TiME) in dMMR CRC is not well understood.

Purpose of the Study:

• To investigate the impact of RAS and BRAF mutations on the tumor immune microenvironment (TiME) in mismatch repair deficient colorectal cancer (dMMR CRC).
• To compare the immunogenicity and inflammatory profiles of dMMR CRC tumors with different mutational statuses (RASmut, BRAFV600E, and wild-type).

Main Methods:

• Retrospective analysis of 448 patients with stage I-IV dMMR CRC.
• Next-generation sequencing (NGS) for tumor mutational burden (TMB) and tumor neoantigen burden (NTB).
• Immunohistochemistry (IHC) for dMMR, PD-L1 expression, and immune cell infiltration (including CD8+ T-cells).

Main Results:

• RAS mutations (RASmut) were found in 22% of dMMR CRC cases, BRAFV600E in 27%, and 51% were double wild-type (RASwt, BRAFwt).
• RASmut tumors exhibited significantly lower NTB and PD-L1 expression compared to BRAFV600E and wild-type tumors.
• The TiME in RASmut dMMR CRC showed reduced overall inflammation and fewer CD8+ T-cell infiltrates than wild-type or BRAFV600E tumors.

Conclusions:

• MSI/dMMR CRCs with RAS mutations are less immunogenic, with a less inflamed TiME compared to wild-type or BRAFV600E tumors.
• These findings suggest distinct immune profiles based on RAS/BRAF mutational status in dMMR CRC.
• Further validation is needed to confirm these immunogenic differences and their clinical implications.