Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Oct 11;14(20):4974.
doi: 10.3390/cancers14204974.

Immune-Checkpoint Inhibitors (ICIs) in Metastatic Colorectal Cancer (mCRC) Patients beyond Microsatellite Instability

Beatrice Borelli  1   2 , Carlotta Antoniotti  1   2 , Martina Carullo  1   2 , Marco Maria Germani  1   2 , Veronica Conca  1   2 , Gianluca Masi  1   2
Affiliations
Review

Immune-Checkpoint Inhibitors (ICIs) in Metastatic Colorectal Cancer (mCRC) Patients beyond Microsatellite Instability

Beatrice Borelli et al. Cancers (Basel). .

Abstract

Immune-checkpoint inhibitors (ICIs) showed impressive results in terms of activity and efficacy in metastatic colorectal cancer (mCRC) patients bearing tumors with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H). Despite that microsatellite status is the major predictive biomarker for the efficacy of ICIs, a proportion of dMMR/MSI-H mCRC tumors do not achieve benefit from immunotherapy due to the primary resistance. Deeper knowledge of biological mechanisms regulating dMMR/MSI-H CRC tumors and immune response may be useful to find new predictive biomarkers of ICIs benefit and tailor the use of immunotherapy even in dMMR/MSI-H mCRC patients. Moreover, several issues are still open, such as the secondary resection of metastases and the optimal duration of ICIs therapy in dMMR/MSI-H mCRC patients. Looking beyond microsatellite status, in a future perspective, several tools (i.e., Tumor Mutational Burden and PD-L1 expression) have been investigated to clarify their possible role as predictive biomarkers. Furthermore, a small subgroup of pMMR/MSS CRC tumors with a POLE mutation of the proofreading domain is characterized by hypermutated phenotype and might derive benefit from immune checkpoint inhibition. In the present work, we aim to review the most recent literature regarding treatment with ICIs in mCRC, focusing on dMMR/MSI-H and special subgroups of CRC patients. Hence, we summarize possible future targets and the most promising predictive biomarkers.

Keywords: POLE mutation; deficient mismatch repair; high microsatellite instability; immune-checkpoint inhibitors; metastatic colorectal cancer.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

References

    1. Hodi F.S., O’Day S.J., McDermott D.F., Weber R.W., Sosman J.A., Haanen J.B., Gonzalez R., Robert C., Schadendorf D., Hassel J.C., et al. Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. N. Engl. J. Med. 2010;363:711–723. doi: 10.1056/NEJMoa1003466. - DOI - PMC - PubMed
    1. Reck M., Rodríguez-Abreu D., Robinson A.G., Hui R., Csőszi T., Fülöp A., Gottfried M., Peled N., Tafreshi A., Cuffe S., et al. Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer. N. Engl. J. Med. 2016;375:1823–1833. doi: 10.1056/NEJMoa1606774. - DOI - PubMed
    1. Rittmeyer A., Barlesi F., Waterkamp D., Park K., Ciardiello F., von Pawel J., Gadgeel S.M., Hida T., Kowalski D.M., Dols M.C., et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): A phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017;389:255–265. doi: 10.1016/S0140-6736(16)32517-X. - DOI - PMC - PubMed
    1. Le D.T., Uram J.N., Wang H., Bartlett B.R., Kemberling H., Eyring A.D., Skora A.D., Luber B.S., Azad N.S., Laheru D., et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N. Engl. J. Med. 2015;372:2509–2520. doi: 10.1056/NEJMoa1500596. - DOI - PMC - PubMed
    1. Alemohammad H., Najafzadeh B., Asadzadeh Z., Baghbanzadeh A., Ghorbaninezhad F., Najafzadeh A., Safarpour H., Bernardini R., Brunetti O., Sonnessa M., et al. The importance of immune checkpoints in immune monitoring: A future paradigm shift in the treatment of cancer. Biomed. Pharmacother. 2021;146:112516. doi: 10.1016/j.biopha.2021.112516. - DOI - PubMed