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Colorectal Cancer Study Reveals Tumor Mutation, Immune Microenvironment Relationships

NEW YORK – An international research team has uncovered apparent ties between tumor mutational patterns and immune features in the surrounding microenvironment in dozens of colorectal cancer (CRC) patients from Korea and Belgium.

"Our collective view of the cellular landscape and intercellular interactions in colorectal cancer provide mechanistic information for the design of efficient immuno-oncology treatment strategies," corresponding authors Woong-Yang Park, a molecular cell biology researcher affiliated with the Samsung Medical Center and Sungkyunkwan University, and Sabine Tejpar, an oncology researcher at KU Leuven, and their colleagues wrote in a study published in Nature Genetics on Monday.

Using single-cell RNA sequencing, the researchers profiled expression patterns in more than 91,100 individual cells from tumor samples from 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.

"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," the researchers reported, adding that "signatures in cancer cells seemed to line up with the presence of particular immune cell populations or stromal cell types in their intercellular network analyses."

The team reasoned that molecular features in the tumor and its microenvironment could both help in selecting the most appropriate treatment for a patient with CRC. Metastatic forms of the disease marked by mismatch repair deficiencies, microsatellite instability, and infiltrating immune cells may be amenable to immunotherapy, for example, and the group reasoned that it may be more broadly beneficial to understand if, and how, tumor features interact with immune and other cells in the microenvironment.

In an effort to tease out these potential interactions, collaborators in Korea used massively parallel single-cell RNA-seq to assess nearly 65,400 individual cells from 23 CRC samples and 10 matched normal samples from 23 Korean patients.

At KU Leuven, investigators used a similar strategy to take a look at the transcriptional profiles in almost 28,000 individual cells from six Belgian CRC patients, focusing on core tumor samples, samples bordering the tumor, and matched normal samples.

"[W]e comprehensively explored the cellular landscape and reconstructed the putative interaction network between tumor cells and their microenvironment," the authors explained. "This collective view allowed us to elucidate how these diverse cellular components jointly determine CRC molecular subtypes in individual patients."

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 researchers dug into those clusters to uncover tumor features that corresponded to heightened or damped down immune responses, along with tumor transcriptional signatures that tended to track with the presence or absence of specific immune or stromal cell types.

They 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.

Even so, the authors noted 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 the such interactions. 

"Once identified," they concluded, "these missing components would complete the translation of cancer cell signatures into a collective CRC landscape."