Immunotherapy for colon cancer: Understanding the reasons behind its inconsistent success
In the realm of cancer treatment, recent advances have made immunotherapy a more promising option. However, its effectiveness varies greatly between different types of colon cancers. A study published on September 14 sheds light on this issue, focusing on the effects of immune therapy on mice with DNA mismatch repair deficiency (MMRd).
The study reveals that immunotherapy is more effective in colon cancer patients with high tumor mutation burden (TMB), such as those with MMRd or microsatellite instability (MSI). These tumors generate a large number of neoantigens, stimulating strong immune cell infiltration and response to immune checkpoint inhibitors (ICIs).
In contrast, colon cancers driven by clonal mutations—which often have a lower overall mutation burden—do not present as many neoantigens and tend to have a more immunosuppressive or "cold" tumor microenvironment. This leads to reduced efficacy of immunotherapy.
Key factors contributing to this difference include the neoantigen load, the tumor immune microenvironment, and immune evasion mechanisms. High TMB tumors produce many neoantigens recognized by T cells, enhancing immune activation and response to ICIs. Clonal mutations, on the other hand, create fewer neoantigens, limiting immune recognition.
Tumors with clonal mutations often lack significant T cell infiltration and may have immune-exclusion features that blunt immunotherapy response, whereas high TMB tumors tend to have abundant tumor-infiltrating lymphocytes (TILs). Clonal mutation-driven tumors might employ alternative immune evasion pathways that render them resistant to immunotherapy.
This explains why clinical trials of immune checkpoint inhibitors show high response rates in dMMR/MSI metastatic colon cancer (high TMB) but limited efficacy in the majority of colon cancers harboring clonal mutations with low mutation burden.
The study also found that mice with clonal mutations were more responsive to immunotherapy than those with subclonal mutations. This suggests that the presence of shared mutations across all cancer cells may play a crucial role in immunotherapy response.
Dr. Anton J. Bilchik, a surgical oncologist, has stated that the new research is timely, as one of the issues with immunotherapy is that it doesn't work in everyone and the response is not always durable. The new data could potentially provide a biomarker to predict immunotherapy response. However, it seems that a high tumor mutation burden may not be the best metric for qualifying people for immunotherapy.
Regardless, it is crucial for anyone over the age of 45 to get screened for colon cancer, regardless of symptoms or risk factors. Ongoing monitoring for colon cancer can include fecal testing, colonoscopy, and sigmoidoscopy.
Risk factors for colon cancer include obesity, smoking, alcohol intake, poor dietary habits, medical conditions like ulcerative colitis, genetic factors, and hereditary conditions. MMRd is a condition that causes tumors to have a high tumor mutation burden, a common occurrence in people with colon cancer.
In conclusion, the effectiveness of immunotherapy in colon cancer treatment depends heavily on the tumor's mutation burden and microenvironment. While tumor mutations may be widespread, they may not be able to trigger an immune response from the body because they're so different from one another. Therefore, understanding these factors can help in the selection of patients for immunotherapy and improve treatment outcomes.
- The study on September 14 reveals that immunotherapy is more effective in colon cancer patients with high tumor mutation burden (TMB), such as those with MMRd or microsatellite instability (MSI).
- A key factor contributing to the effectiveness of immunotherapy in high TMB colon cancers is the neoantigen load, as these tumors generate a large number of neoantigens, stimulating strong immune cell infiltration and response to immune checkpoint inhibitors (ICIs).
- In contrast, colon cancers driven by clonal mutations, which often have a lower overall mutation burden, do not present as many neoantigens and tend to have a more immunosuppressive or "cold" tumor microenvironment, leading to reduced efficacy of immunotherapy.
- Regardless of the tumor mutations, it is crucial for anyone over the age of 45 to get screened for colon cancer, as risk factors for colon cancer include obesity, smoking, alcohol intake, poor dietary habits, medical conditions like ulcerative colitis, genetic factors, and hereditary conditions, with MMRd being a condition causing tumors to have a high tumor mutation burden, a common occurrence in people with colon cancer.
