Related Experiment Video
Updated: Aug 17, 2026
Detection of a Circulating MicroRNA Custom Panel in Patients with Metastatic Colorectal Cancer
Published on: March 14, 2019
Immune Checkpoint Inhibitors in pMMR Metastatic Colorectal Cancer: A Tough Challenge
Federica Marmorino1,2, Alessandra Boccaccino1,2, Marco Maria Germani1,2
1Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, via Risorgimento 36, 56126 Pisa, Italy.
Abstract:
The introduction of checkpoint inhibitors provided remarkable achievements in several solid tumors but only 5% of metastatic colorectal cancer (mCRC) patients, i.e., those with bearing microsatellite instable (MSI-high)/deficient DNA mismatch repair (dMMR) tumors, benefit from this approach. The favorable effect of immunotherapy in these patients has been postulated to be due to an increase in neoantigens due to their higher somatic mutational load, also associated with an abundant infiltration of immune cells in tumor microenvironment (TME). While in patients with dMMR tumors checkpoint inhibitors allow achieving durable response with dramatic survival improvement, current results in patients with microsatellite stable (MSS or MSI-low)/proficient DNA mismatch repair (pMMR) tumors are disappointing. These tumors show low mutational load and absence of "immune-competent" TME, and are intrinsically resistant to immune checkpoint inhibitors. Modifying the interplay among cancer cells, TME and host immune system is the aim of multiple lines of research in order to enhance the immunogenicity of pMMR mCRC, and exploit immunotherapy also in this field. Here, we focus on the rationale behind ongoing clinical trials aiming at extending the efficacy of immunotherapy beyond the MSI-high/dMMR subgroup with particular regard to academic no-profit studies.
Insights
Checkpoint inhibitors benefit only 5% of metastatic colorectal cancer (mCRC) patients with microsatellite instability-high (MSI-high)/mismatch repair-deficient (dMMR) tumors. Research aims to extend immunotherapy efficacy to microsatellite-stable (MSS) mCRC patients.
Area of Science:
- Oncology
- Immunotherapy
- Cancer Research
Background:
- Checkpoint inhibitors show remarkable efficacy in several solid tumors.
- However, only 5% of metastatic colorectal cancer (mCRC) patients, specifically those with microsatellite instability-high (MSI-high)/mismatch repair-deficient (dMMR) tumors, benefit from this therapy.
- This limited benefit is attributed to higher neoantigen load and immune cell infiltration in dMMR tumors, contrasting with the low immunogenicity and resistance observed in microsatellite-stable (MSS) or mismatch repair-proficient (pMMR) mCRC.
Purpose of the Study:
- To explore strategies for enhancing the immunogenicity of pMMR mCRC.
- To investigate the rationale behind ongoing clinical trials aimed at extending immunotherapy efficacy to a broader mCRC patient population.
- To focus on academic, non-profit studies in this research area.
Main Methods:
- Review of current understanding of tumor microenvironment (TME) and immunogenicity in different mCRC subtypes.
- Analysis of the mechanisms underlying response and resistance to checkpoint inhibitors.
- Focus on ongoing clinical trials, particularly non-profit academic studies, exploring novel therapeutic approaches.
Main Results:
- Current immunotherapy approaches are highly effective in MSI-high/dMMR mCRC, leading to durable responses and improved survival.
- Microsatellite-stable (MSS) or mismatch repair-proficient (pMMR) mCRC tumors are largely resistant to checkpoint inhibitors due to low mutational load and an "immune-excluded" TME.
- Multiple research efforts are underway to modify the cancer cell, TME, and host immune system interplay to overcome resistance in pMMR mCRC.
Conclusions:
- Extending the benefits of immunotherapy beyond the MSI-high/dMMR subgroup in mCRC remains a significant challenge.
- Novel therapeutic strategies are crucial to enhance the immunogenicity of pMMR mCRC and improve patient outcomes.
- Ongoing academic research holds promise for developing new approaches to harness immunotherapy for a wider range of mCRC patients.
