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

Borelli, Beatrice; Antoniotti, Carlotta; Carullo, Martina; Germani, Marco Maria; Conca, Veronica; Masi, Gianluca

doi:10.3390/cancers14204974

Cited by 62Cancer Immunotherapy and BiomarkersColorectal Cancer Treatments and StudiesGenetic factors in colorectal cancer

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

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Borelli, Beatrice, Antoniotti, Carlotta, Carullo, Martina, Germani, Marco Maria, Conca, Veronica, Masi, Gianluca·2022·Cancers

DOI 10.3390/cancers14204974PMC PMC9599678

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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.

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Despite high rates of durable responses, a fraction of dMMR/MSI-H colorectal cancer patients treated with ICIs develop immune resistance, approximately 15-29%.
“However, despite the high rate of durable responses, a fraction of them will develop immune resistance that can outweigh prolonged survival outcomes (approximately 15–29%) [12,15,16].”
From Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy (2024) · cites this paper as [12]
The dMMR/MSI-H phenotype has increased immunogenic properties inducing high immune cell infiltration, particularly from tumor-infiltrating lymphocytes.
“Nonetheless, it has been proved that this phenotype also has increased immunogenic properties inducing high immune cell infiltration, particularly from tumor-infiltrating lymphocytes [12,43].”
From Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy (2024) · cites this paper as [12]
The immune sensitivity of the dMMR/MSI-H molecular subset is attributed to high mutational burden from MMR deficiency, resulting in augmented presentation of immunogenic neoantigens and a rich tumor microenvironment infiltrated by immune cells.
“Therefore, this molecular subset’s immune sensitivity is attributed to the high mutational burden from MMR deficiency, resulting in an augmented presentation of immunogenic neoantigens and a rich tumor microenvironment infiltrated by immune cells [12].”
From Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy (2024) · cites this paper as [12]

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Background
Immune profiling of microsatellite instability-high and polymerase ε (POLE)-mutated metastatic colorectal tumors identifies predictors of response to anti-PD-1 therapy
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Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy
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Authors: Borelli, B., Antoniotti, C., Carullo, M., Germani, M. M., Conca, V., & Masi, G.
Affiliations: University of Pisa (IT)
Corresponding author: Antoniotti, Carlotta
ORCID: Borelli, Beatrice
Antoniotti, Carlotta
Carullo, Martina
Germani, Marco Maria
Conca, Veronica
Masi, Gianluca
Venue: Cancers
Publisher: MDPI AG
Published: 2022-10-11
Volume: 14
Issue: 20
Pages: 4974
ISSN: 2072-6694 (ISSN-L)
DOI: 10.3390/cancers14204974
PMC: PMC9599678
OpenAlex: W4304585144
Cited by: 62
References: 79
Citations by year: 2026: 12 · 2025: 19 · 2024: 17 · 2023: 14
FWCI: 1.53
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Cancers (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion, cc-by)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics: Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
Keywords: immune checkpoint inhibitors, metastatic colorectal cancer, microsatellite instability, mismatch repair deficiency, predictive biomarkers, tumor mutational burden, PD-L1 expression, POLE mutation, immunotherapy resistance, treatment duration

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

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