Immune Checkpoint Inhibition in Metastatic Colorectal Cancer Harboring Microsatellite Instability or Mismatch Repair Deficiency

Abstract

Microsatellite instability (MSI) is a tumor phenotype related to a deficient DNA mismatch repair system (dMMR). This phenotype, observed in 5% of metastatic mCRC but 10–18% of localized CRC, is associated with high tumor mutational burden with highly immunogenic neoantigens. It has emerged as a major predictive biomarker for the efficacy of ICIs. In this review, we will present a comprehensive overview of the literature concerning the efficacy of ICIs in MSI/dMMR mCRC, with a focus on new developments in first-line metastatic setting. Then, we will present current and future challenges of immuno-oncology for patients with MSI/dMMR metastatic CRC.

Mechanisms of Immune Escape and Resistance to Checkpoint Inhibitor Therapies in Mismatch Repair Deficient Metastatic Colorectal Cancers

“…A considerable number of MSI mCRC patients exhibit primary resistance to CPIs and another portion will develop secondary resistance mechanisms leading to disease progression [ 121 ]. Based on these observations, even if supporting data from translational studies are still lagging behind, several ongoing clinical trials are trying to bypass this limitation by exploiting combinations of CPIs with targeted agents (such as KRAS or BRAF inhibitors) or with cytotoxic agents and/or radiotherapy ( Table 1 ).…”

“…In conclusion, despite CPIs having revolutionized the landscape of treatment of MSI mCRC, new approaches combining different strategies are likely to boost the effectiveness of immunotherapy in this peculiar subset of patients. However, despite recent efforts, robust data from preclinical and translational studies as well as from early clinical trials are still lacking [ 121 ]. Different combinatorial approaches are currently under investigation ( Table 1 ), and many others are likely to emerge based on preclinical elucidation of resistance mechanisms to CPIs.…”

“…However, despite remarkable PFS and duration of response (DOR), 29.4% of patients exhibited primary resistance to pembrolizumab, compared to 12.3% of those enrolled in the standard treatment arm [ 79 ]. On the other hand, initial results from patients treated with the combination of nivolumab plus ipilimumab indicated that around 13% of MSI CRC patients exhibit primary resistance to therapy [ 119 , 120 , 121 ]. Further promising data from another phase III trial investigating the combination of nivolumab and ipilimumab (NCT04008030) in the same first-line setting are expected soon.…”

Integrated Profiling Identifies PLOD3 as a Potential Prognostic and Immunotherapy Relevant Biomarker in Colorectal Cancer

“…OBSCN ( 47 ) was significantly associated favorable prognosis, immune-hot subtype and potentially better immunotherapeutic efficacy, which was consistent with more immune infiltration in PLOD3 -low group. Moreover, negative correlations were observed between PLOD3 expression and multiple immune related genes ( 48 , 49 ), suggesting that PLOD3 plays a negative role in regulating tumor immunology. Several indicators for immunotherapy response have been identified in CRC, such as TMB ( 50 , 51 ) and MSI ( 52 , 53 ) status.…”

Tackling Refractory Metastatic Colorectal Cancer: Future Perspectives

“…Herein we present the standard treatment options for refractory metastatic CRC (mCRC), and we discuss the latest research developments that may represent, pending data confirmation and/or regulatory approval, novel therapeutic options and innovative strategies in this setting. The immunological characterization of CRC and potential immunotherapeutic strategies have been reviewed elsewhere [ 9 ].…”