Tumor Mutation and Immune Microenvironment Revealed in Colorectal Cancer

Most colorectal cancers are due to old age and lifestyle factors, with only a small number of cases due to underlying genetic disorders. Other risk factors include diet, obesity, smoking, and lack of physical activity. Dietary factors that increase the risk include red meat, processed meat, and alcohol.

Immunotherapy for metastatic colorectal cancer (CRC) is effective only for mismatch repair-deficient tumors with high microsatellite instability that demonstrate immune infiltration, suggesting that tumor cells can determine their immune microenvironment. Immune checkpoint inhibitors have demonstrated impressive activity in patients with CRC and other solid tumors.

An international team of scientists collaborating with the Sungkyunkwan University School of Medicine (Suwon, Korea) used single-cell RNA sequencing, and profiled expression patterns in more than 91,100 individual cells from tumor samples. This included 23 Korean individuals with CRC and six CRC patients from Belgium, bringing in additional genome sequence and genotyping data to explore the relationships between immune or stromal cell features in the context of tumor mutation drivers, mutational signatures, and cell lineage patterns. At Katholieke Universiteit Leuven (Leuven, Belgium), investigators used a similar strategy to take a look at the transcriptional profiles in almost 28,000 individual cells from the Belgian CRC patients, focusing on core tumor samples, samples bordering the tumor, and matched normal samples.

The team reported that cancer cells displayed transcriptional features reminiscent of normal differentiation programs, and genetic alterations that apparently fostered immunosuppressive microenvironments directed by regulatory T cells, myofibroblasts and myeloid cells. Intercellular network reconstruction supported the association between cancer cell signatures and specific stromal or immune cell populations.

The investigators noted that tumors classified in a consensus molecular subtype (CMS) called CMS2 often contained TP53 or APC driver mutations and had relatively low levels of immune cells and stromal cells, for example, along with gene expression signatures resembling absorptive cell lineages. Based on data for 91,103 unsorted single cells from patients in the two cohorts, the team teased out expression-based clusters representing cell types in the microenvironment, including stromal, epithelial, myeloid, and mast cells, along with T cells and B cells, in samples collected from different parts of the large intestine.

The authors concluded that that the genetic alterations found in the tumors did not fully line up with molecular features in the samples, suggesting still other environmental, microbiome, or molecular features contribute to such interactions. Once identified, these missing components would complete the translation of cancer cell signatures into a collective CRC landscape. The study was published on May 25, 2020 in the journal Nature Genetics.

Related Links:
Sungkyunkwan University School of Medicine
Katholieke Universiteit Leuven