Resolving the difference between left-sided and right-sided colorectal cancer by single-cell sequencing

Area of Science:

• Oncology
• Immunology
• Genomics

Background:

• Colorectal cancer (CRC) exhibits distinct characteristics based on tumor location.
• Understanding molecular differences between left-sided and right-sided CRC is crucial for targeted therapies.

Purpose of the Study:

• To compare the transcriptomes of single cells from left-sided and right-sided CRC.
• To identify molecular markers associated with prognosis and immunotherapy response in CRC.

Main Methods:

• Single-cell RNA sequencing (scRNA-Seq) was performed on 27,927 CRC cells from 6 patients (3 left-sided, 3 right-sided).
• Differential gene expression and cell-type analysis were conducted to compare tumor microenvironments.

Main Results:

• Right-sided CRC had a higher proportion of exhausted, migratory CD8+ T cells.
• Left-sided CRC displayed a favorable prognostic T cell cluster (pre-exhausted/exhausted) and a novel RBP4+NTS+ cancer cell subpopulation.
• Regulatory T cells (Tregs) in left-sided CRC showed increased immunotherapy-related gene expression.
• Left-sided CRC exhibited enhanced M2-like macrophage-mediated antibody-dependent cellular phagocytosis (ADCP) and cytotoxicity (ADCC), correlating with good prognosis.

Conclusions:

• Tumor location significantly influences the immune microenvironment and molecular profiles in colorectal cancer.
• Left-sided CRC may be more responsive to immunotherapy due to distinct T cell populations and Treg gene expression.
• Specific macrophage functions (ADCP/ADCC) are associated with favorable outcomes in left-sided CRC.