The tumor microenvironment and Immunoscore are critical determinants of dissemination to distant metastasis

Area of Science:

• Oncology
• Cancer Biology
• Immunology

Background:

• Distant metastases are the primary cause of cancer-related deaths, yet the mechanisms driving or inhibiting this process remain unclear.
• Understanding metastasis is crucial for improving patient outcomes in colorectal cancer (CRC).

Purpose of the Study:

• To investigate the impact of genetic mutations, genomic instability, vascularization, and the tumor immune microenvironment on synchronous metastasis in colorectal cancer.
• To identify key factors that promote or inhibit the development of distant metastases.

Main Methods:

• Analysis of large cohorts of colorectal cancer patients.
• Assessment of tumor genetic heterogeneity, chromosomal instability, cancer-associated mutations, and gene expression.
• Evaluation of lymphatic and blood vascularization, and immune cell infiltration (Immunoscore).

Main Results:

• No significant association found between genomic instability or key mutations and metastasis stage (M stage).
• FBXW7 mutations correlated with an absence of metastasis and enhanced T cell activity.
• Decreased lymphatic vessels and reduced immune cytotoxicity were identified as hallmarks of the metastatic process.
• The Immunoscore and increased marginal lymphatic vessels demonstrated a protective effect against distant metastases.

Conclusions:

• Tumor microenvironment factors, specifically immune cytotoxicity and lymphatic vessel presence, are critical in preventing colorectal cancer metastasis.
• FBXW7 mutations may confer a protective role against metastasis by modulating the immune response.
• Genomic instability does not appear to be a primary driver of synchronous metastasis in this CRC cohort.