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Review
. 2023 Jan 30;15(3):863.
doi: 10.3390/cancers15030863.

Current Landscape and Potential Challenges of Immune Checkpoint Inhibitors in Microsatellite Stable Metastatic Colorectal Carcinoma

María San-Román-Gil  1 , Javier Torres-Jiménez  2 , Javier Pozas  1 , Jorge Esteban-Villarrubia  3 , Víctor Albarrán-Fernández  1 , Pablo Álvarez-Ballesteros  1 , Jesús Chamorro-Pérez  1 , Diana Rosero-Rodríguez  1 , Inmaculada Orejana-Martín  1 , Íñigo Martínez-Delfrade  1 , Pablo Reguera-Puertas  1 , Raquel Fuentes-Mateos  1 , Reyes Ferreiro-Monteagudo  1
Affiliations
Review

Current Landscape and Potential Challenges of Immune Checkpoint Inhibitors in Microsatellite Stable Metastatic Colorectal Carcinoma

María San-Román-Gil et al. Cancers (Basel). .

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.

Keywords: MSS; POLE/POLD1; TMB; biomarkers; immune checkpoint inhibitors (ICI); immunoscore; metastatic colorectal carcinoma (mCRC); microbiome; pMMR.

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Conflict of interest statement

Reyes Ferreiro-Monteagudo: Amgen, Roche Pharma, Pierre Fabre (C/A), Amgen, Servier, Merck, Roche Pharma, Bayer Hispania, Pierre Fabre (SH) The rest of the authors declares no conflict of interest. (C/A): Consulting/Advisory relationship; (SH) Speaker Honorarium.

Figures

Figure 1
Figure 1
Among the current challenges described in combination with ICIs, we can distinguish the use of therapies that aim to release neoantigens to activate the immune system, such as chemotherapy (CT), targeted therapy, or radiotherapy (RT). Other methods to cope with the inherent resistance to ICIs, such as temozolomide (TMZ) or PARP inhibitors (PARPi), operate by creating a temporary MSI status. The use of tyrosine-kinase inhibitors (TKIs) that target VEGFR in combination with ICIs has had favorable results in other malignancies, with modulation over the TME in addition to the known antitumoral effect. Additionally, blocking TGF- β and VEGF may have a role in promoting ICI activity in these tumors. Meanwhile, there are rationales for combination with inhibitors of the main steps of the MAPK or PIC3KA pathways.
See this image and copyright information in PMC

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