'Different for Each Person' Colon Cancer Immunotherapy Effects... Korean Researchers Identify the Cause.

Professor Kim Jeong-ho of Seoul National University and Professor Kim Sang-woo of Yonsei University Joint Research Team

▲Regular endoscopic examinations are important for the prevention of colorectal cancer. [Photo by Gangdong Kyung Hee University Hospital]

[Asia Economy Reporter Kim Bong-su] Korean researchers have developed a technology that can significantly improve the accuracy of colorectal cancer treatment through immunotherapy. They identified the reasons why responses to immunotherapy vary among individuals with colorectal cancer, providing important clues to the effectiveness of immune checkpoint inhibitor therapy.

The Korea Research Foundation announced on the 26th that a joint research team led by Professor Kim Jeong-ho of Seoul National University and Professor Kim Sang-woo of Yonsei University confirmed that the actual immune response varies greatly even in certain types of colorectal cancer known to respond well to immunotherapy, and newly discovered the causes of these differences in responsiveness.

The most well-known biomarker for response to colorectal cancer immunotherapy is microsatellite instability (MSI). When microsatellite instability is present, the number of genetic mutations in cancer cells increases significantly, leading to a strong immune response and thus a better response to immune checkpoint inhibitor therapy. However, there are cases where the effect of immunotherapy is poor despite the presence of microsatellite instability, and the reasons for this have not been well understood.

The research team collected 73 cases of microsatellite instability colorectal cancer tissues and analyzed the tumor immune microenvironment characteristics using immunohistochemical staining and digital image analysis techniques. Contrary to expectations, they confirmed that the degree of immune response in these colorectal cancers varied widely, with some showing very low immune responses. Furthermore, to identify the genetic characteristics of groups with high and low immune responses, they conducted bioinformatics analysis using next-generation sequencing (NGS) and found that the number of mutations, a known feature of microsatellite instability colorectal cancer, was unrelated to the immune response. This conclusion completely deviates from previous expectations.

＜Schematic Diagram Proposing a More Detailed Classification of Colorectal Cancer (Microsatellite Instability Colorectal Cancer)＞

Microsatellite instability colorectal cancer can generally be divided into a group with high immune response and a group with low immune response, contrary to expectations. (High immunity vs. Low immunity) Among these, the low immunity group can be further subdivided into subgroups according to the colorectal cancer molecular classification called CMS.
These three subgroups show no difference in mutation burden but exhibit distinct characteristics in gene expression and other factors, allowing the identification of candidate therapeutic targets tailored to the characteristics of each subgroup.

/Figure description and provided by Professor Jeongho Kim, Department of Pathology, Seoul National University Hospital

The research team particularly found that histological types of tumors, such as mucinous types, the presence or absence of mutations in the tumor gene KRAS, and the activation status of signaling pathways involved in cell proliferation (Wnt and Notch) were important factors. Based on this, they newly classified microsatellite instability colorectal cancer and identified angiogenesis-related molecules and immune-related molecules that could serve as therapeutic targets.

The research team stated, "This is the first study to elucidate differences in immune responses in microsatellite instability-positive colorectal cancer at the genomic level," adding, "Now that we understand the limitations of currently used clinical biomarkers, we expect to improve the accuracy of immune checkpoint inhibitor therapy using the newly identified composite markers."

The results of this study were published on the 13th in the international journal in the field of tumor immunology, the Journal for ImmunoTherapy of Cancer.

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