Interrogating the immune landscape of microsatellite stable RAS-mutated colon cancer

Area of Science:

• Oncology
• Immunology
• Genomics

Background:

• RAS-mutated (RASmt) microsatellite stable (MSS) colon cancer (CC) presents a unique challenge due to its typically non-immunogenic profile.
• Understanding the immune microenvironment is crucial for developing effective treatment strategies for this subtype of colon cancer.

Purpose of the Study:

• To investigate the immune microenvironment characteristics of RAS-mutated, microsatellite stable colon cancer.
• To identify potential biomarkers and patient subsets that may respond to immunotherapy.

Main Methods:

• Retrospective analysis of 161 early-stage and 121 metastatic colon cancer patients with RAS mutations and MSS status.
• Utilized whole exome sequencing, RNA sequencing, digital pathology, and immune marker analysis.
• Assessed Immunoscore (IS), Tumor Lymphocytes Infiltrating Score (TuLIS), and Immunoscore Immune-Checkpoint (ISIC) scores.

Main Results:

• A small fraction of tumors showed a highly infiltrated immune microenvironment, correlating with high IS and TuLIS scores.
• 52% of tumors exhibited high ISIC scores, showing similar microenvironment composition to IS-high and TuLIS-high tumors.
• High ISIC scores were associated with increased tumor mutational burden compared to ISIC-low tumors.

Conclusions:

• A significant proportion of MSS RASmt colon cancers display high ISIC scores, indicating potential immunogenicity.
• These findings support the evaluation of MSS RASmt CC in prospective immunotherapy combination trials.