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Current Landscape and Potential Challenges of Immune Checkpoint Inhibitors in Microsatellite Stable Metastatic
María San-Román-Gil1, Javier Torres-Jiménez2, Javier Pozas1
1Medical Oncology Department, Ramón y Cajal University Hospital, 28034 Madrid, Spain.
Abstract:
Colorectal cancer (CRC) is the third most frequent cancer and the second most common cause of cancer-related death in Europe. High microsatellite instability (MSI-H) due to a deficient DNA mismatch repair (dMMR) system can be found in 5% of metastatic CRC (mCRC) and has been established as a biomarker of response to immunotherapy in these tumors. Therefore, immune checkpoint inhibitors (ICIs) in mCRC with these characteristics were evaluated with results showing remarkable response rates and durations of response. The majority of mCRC cases have high levels of DNA mismatch repair proteins (pMMR) with consequent microsatellite stability or low instability (MSS or MSI-low), associated with an inherent resistance to ICIs. This review aims to provide a comprehensive analysis of the possible approaches to overcome the mechanisms of resistance and evaluates potential biomarkers to establish the role of ICIs in pMMR/MSS/MSI-L (MSS) mCRC.
Insights
High microsatellite instability (MSI-H) colorectal cancer (CRC) responds well to immunotherapy. This review explores strategies to improve immunotherapy effectiveness in microsatellite stable (MSS) metastatic CRC, overcoming resistance mechanisms.
Area of Science:
- Oncology
- Cancer Research
- Immunotherapy
Background:
- Colorectal cancer (CRC) is a leading cause of cancer death in Europe.
- High microsatellite instability (MSI-H) due to deficient DNA mismatch repair (dMMR) is a biomarker for immunotherapy response in metastatic CRC (mCRC).
- The majority of mCRC cases are microsatellite stable (MSS) and inherently resistant to immunotherapy.
Purpose of the Study:
- To review the efficacy of immune checkpoint inhibitors (ICIs) in MSI-H mCRC.
- To analyze approaches for overcoming ICI resistance in MSS mCRC.
- To identify potential biomarkers for ICI therapy in MSS mCRC.
Main Methods:
- Literature review of studies evaluating ICIs in mCRC.
- Analysis of mechanisms of ICI resistance in MSS mCRC.
- Evaluation of emerging biomarkers and therapeutic strategies.
Main Results:
- ICIs show remarkable response rates and durations in MSI-H mCRC.
- MSS mCRC exhibits inherent resistance to current ICI therapies.
- Novel strategies are being investigated to sensitize MSS mCRC to ICIs.
Conclusions:
- Immunotherapy is highly effective in MSI-H mCRC.
- Overcoming ICI resistance in MSS mCRC is a critical unmet need.
- Further research into biomarkers and combination therapies is essential for MSS mCRC treatment.
