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Immune Checkpoint Inhibitors in pMMR/MSS Colorectal Cancer
Joanna El Hajj1,2, Sarah Reddy1, Nilesh Verma1,2
1Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA.
Background:
Immune checkpoint inhibitors have recently replaced over chemotherapy as the first-line treatment for microsatellite instability-high or mismatch repair deficient (dMMR/MSI-H) stage 4 colorectal cancers. Considering this success, many studies have tried to replicate the use of immune checkpoint inhibitors, either as a single agent or in combination with other therapeutic agents, in the treatment of proficient mismatch repair (pMMR/MSS) stage 4 colorectal cancers. This review summarizes the seminal clinical data about the immune checkpoint inhibitors used in pMMR/MSS colorectal cancers and some future directions.
Results:
Studies concerning the use of immune checkpoint inhibitors as a single agent or in combination with other immune checkpoint inhibitors, targeted therapy, chemotherapy, or radiotherapy have proven inefficient in the treatment of pMMR/MSS colorectal cancer. However, a small subset of patients with pMMR/MSS colorectal cancer who has a mutation in POLE and POLD1 enzymes may respond to immunotherapy. Moreover, patients without liver metastasis appear to have a better chance of response. New immune checkpoint targets are being identified, such as VISTA, TIGIT, LAG3, STING signal pathway, and BTLA, and studies are ongoing to determine their efficiency in this disease type.
Conclusion:
Immune checkpoint inhibitor-based regimens have not yet shown any meaningful positive outcomes for most pMMR/MSS colorectal cancers. A beneficial effect among a minority of these patients has been observed, but concrete biomarkers of response are lacking. Understanding the underlying mechanisms of immune resistance should guide further research for overcoming these obstacles.
Insights
Immune checkpoint inhibitors are ineffective for most proficient mismatch repair (pMMR/MSS) colorectal cancers. A small subset with POLE/POLD1 mutations may benefit, but biomarkers are needed.
Area of Science:
- Oncology
- Immunotherapy
- Gastrointestinal Cancers
Background:
- Immune checkpoint inhibitors (ICIs) are first-line for dMMR/MSI-H stage 4 colorectal cancer.
- Research is exploring ICI efficacy in proficient mismatch repair (pMMR/MSS) stage 4 colorectal cancers.
- This review covers clinical data and future directions for ICIs in pMMR/MSS colorectal cancer.
Purpose of the Study:
- To review clinical data on ICIs in pMMR/MSS stage 4 colorectal cancer.
- To summarize findings on ICI efficacy and identify potential responders.
- To discuss future research directions and novel targets.
Main Methods:
- Review of seminal clinical data on ICIs in pMMR/MSS colorectal cancer.
- Analysis of studies using ICIs as single agents or in combination therapies.
- Identification of potential predictive biomarkers and novel ICI targets.
Main Results:
- ICIs, alone or combined, show limited efficacy in pMMR/MSS colorectal cancer.
- A subset of patients with POLE/POLD1 mutations may respond to immunotherapy.
- Absence of liver metastasis and new targets like VISTA, TIGIT, LAG3 suggest potential avenues.
Conclusions:
- ICI-based regimens lack meaningful outcomes for most pMMR/MSS colorectal cancers.
- A minority of patients show benefit, but response biomarkers are absent.
- Further research into immune resistance mechanisms is crucial for therapeutic advancement.
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