Research Reveals the Cause of Low Effectiveness of Immunotherapy in Colon Cancer
A groundbreaking study has been published in the prestigious academic journal ‘Nature Genetics’, shedding light on why immunotherapy is less effective in treating colon cancer compared to other types of cancer. The research, conducted on mice, identified a specific DNA repair deficiency called mismatch repair deficiency (MMRd) as the main culprit behind this disparity.
MMRd prevents the immune system from rectifying replication errors in a cell’s DNA, leading to the accumulation of mutations in tumor cells. These mutations, known as “tumour mutational burden (TMB),” are commonly observed in human colon cancer cells. It was previously believed that these mutations could generate new antigens, enabling the immune system to detect and eliminate tumor cells effectively. However, the recent study disproved this assumption.
The researchers likened tumors with low mutations to trees with a single central trunk, while tumors with high TMB resembled bushes spreading in various directions. Consequently, tumor cells with high TMB only share a small portion of their mutations, resulting in a diverse composition of mutations within the tumor. This heterogeneity makes it challenging for the immune system to mount an effective response.
Interestingly, the study found that tumors containing identical cells with replication mutations exhibited a stronger response to immunotherapy. This aligns with the hypothesis that tumors with similar mutations are more likely to respond positively to immunotherapy. Conversely, those with a heterogeneous mutation composition may experience diminished efficacy.
These groundbreaking findings have significant implications for personalized treatment strategies for patients with colorectal cancer. Currently, the US Food and Drug Administration (FDA) recommends immunotherapy as a potential treatment for patients with a high tumor mutational burden. However, due to the emerging evidence suggesting the predictive power of various biomarkers, including MMRd, there is a growing call for revising the existing treatment guidelines.
Colon cancer ranks as the third most common cancer in the United States, and several risk factors contribute to its prevalence, including obesity, smoking, alcohol consumption, certain dietary patterns like processed meat intake, pre-existing conditions like ulcerative colitis, and genetic predisposition. It is worth noting that regular health check-ups, including stool tests, colonoscopies, and sigmoidoscopies, are recommended for all adults over the age of 50, regardless of symptoms or risk factors.
As further research unfolds in this field, it is expected that these findings will pave the way for improved treatment approaches and enhanced patient outcomes.
By Han Ji-hyuk, Medical Today Reporter (hanjh3438@mdtoday.co.kr)
[Copyrightⓒ Medical Today. Unauthorised reproduction and redistribution prohibited]
▲ Research results were published which identified the cause of the low effectiveness of immunotherapy in colon cancer. (Photo = DB)
[메디컬투데이=한지혁 기자] Research results have been published which identified the cause of the low effectiveness of immunotherapy in colon cancer.
The results of a mouse study which identified why immunotherapy for colon cancer is less effective than other cancers have been published in the academic journal ‘Nature Genetics’.
Recently, a research team analyzed the effects of immunotherapy in mice with DNA mismatch repair deficiency (MMRd), which prevents the immune system from correcting replication errors in a cell’s DNA.
MMRd can cause mutations in tumor cells, causing an increase in ‘tumour mutational burden (TMB)’. MMRd and TMB are known to be commonly observed in human colon cancer cells. The conventional wisdom is that the mutations caused by MMRd could produce new antigens, which could allow the immune system to better recognize tumor cells and generate a positive immune response. However, the researchers confirmed that this was not the case.
The researchers compared tumors with few mutations to trees with everything growing from one central trunk, while tumors with high TMB were compared to bushes that spread out in many directions. Thus, the tumor-forming cells with high TMB share only a small fraction of their mutations, and each has a very different composition of mutations.
If the types of mutations each cancer cell has are too different, it is difficult to generate an effective immune response. In fact, tumors containing identical cells with replication mutations showed a stronger response to immunotherapy.
This supports the hypothesis that tumors with similar mutations have a better response to immunotherapy, but that a heterogeneous mutation composition may have a negative impact on the efficacy of immunotherapy.
These research results may help provide personalized treatment for colorectal cancer patients. Currently, US Food and Drug Administration (FDA) guidelines recommend that patients with a high tumor mutational burden should be potential targets for immunotherapy.
However, as it has recently become known that various biomarkers, including MMRd, can help predict the effectiveness of immunotherapy, there are increasing voices calling for revision of the current guidelines.
Colon cancer is the third most common cancer in the United States, and obesity, smoking, drinking, eating habits such as eating processed meat, diseases including ulcerative colitis, and genetic factors can act as risk factors.
Even if there are no symptoms or risk factors, it is recommended that all adults over the age of 50 have regular health checkups, which include stool tests, colonoscopy, and sigmoidoscopy.
Medical Today Reporter Han Ji-hyuk (hanjh3438@mdtoday.co.kr)
[저작권자ⓒ 메디컬투데이. 무단전재-재배포 금지]
#immunotherapy #work #colon #cancer
