Cancer Genetics and Epigenetics 2024, Vol.12, No.5, 234-253 http://medscipublisher.com/index.php/cge 244 colorectal cancer is still fraught with problems. Although FDA approved pembrolizumab for advanced solid tumors with TMB-high according to KEYNOTE-158 clinical trial, there was none CRC patients in the clinical trial (Marabelle et al., 2020). Besides, the lack of adequate standards for optimal TMB cut-off still remains concern (Marques et al., 2024). 6.1.3 PD-L1 expression PD-L1 expression in tumor cells and tumor-infiltrating immune cells is a common predictive biomarker for immunotherapy in various tumor types, but its role in CRC remains unclear. The substantial intra-tumor heterogeneity of PD-L1 expression complicates its detection. Besides, standardization and threshold setting for PD-L1 expression assays remain controversial. 6.2 Biomarkers of immune cell infiltration The presence and density of tumor-infiltrating lymphocytes (TILs), particularly CD8+ T cells, in the tumor microenvironment are critical indicators of the immune system's engagement with the tumor. High levels of TILs are associated with better responses to immunotherapy (Giatromanolaki et al., 2023). Quantification of TILs can be performed using techniques such as immunohistochemistry and digital pathology, which provide valuable prognostic and predictive information (Cao et al., 2022). 6.3 Predictive biomarkers from peripheral blood Non-invasive biomarkers from peripheral blood, such as circulating tumor DNA (ctDNA), immune cell profiles, and metabolic signatures, are being explored for their potential to predict responses to immunotherapy. For example, higher levels of specific immune cells, such as CD8+ T cells, and metabolic markers have been linked to better responses to treatment. Monitoring these biomarkers can provide real-time insights into the patient's immune status and treatment efficacy (Nixon et al., 2019; Triozzi et al., 2022). 6.4 Imaging biomarkers Imaging biomarkers, such as radiomics, utilize advanced imaging techniques combined with artificial intelligence to predict responses to immunotherapy. For instance, radiomic features derived from CT or PET scans can provide information on tumor heterogeneity, immune infiltration, and metabolic activity. These non-invasive biomarkers are valuable for assessing the tumor's immunogenic profile and predicting therapeutic outcomes, which still needs to be validated with larger samples in the future (Sun et al., 2018; Trebeschi et al., 2019) . 6.5 Specific gene mutation 6.5.1 POLE mutation Polymerase ε (POLE), encoded by the POLEgene, plays an essential role in DNA replication and proofreading in cells, and has recently been proposed to be involved in the efficacy of immunotherapy (Garmezy et al., 2022). The association of POLE mutations with immunotherapy remission has been observed in clinical experience (Bikhchandani et al., 2023; Durando et al., 2022). Somatic POLE mutations are detected in approximately 1% of all CRC patients (Kawai et al., 2021; Ma et al., 2022). Further studies with large cohorts and long-term follow-up are critical to determine the role of POLE mutations as predictive markers of ICB efficacy in CRC treatment. 6.5.2 BRAF mutation BRAF V600E mutations are associated with unfavorable clinical prognosis in CRC patients. The results of a clinical study combining the BRAF inhibitor darafenib, the MEK inhibitor trametinib, and the immunotherapeutic agent spartalizumab for BRAF V600E mutation CRC patients found a very good response rate (24.3% of all patients; 25% of microsatellite-stabilized patients) (Tian et al., 2023). Despite the small number of patients with BRAF mutations, this may still provide direction for the future search for immunotherapy biomarkers. 6.6 Gut microbiota Recent studies have emphasized the potential of gut microbiota composition in predicting ICB responses in CRC patients. Interactions between the gut microbiota and colorectal cancer pathogenesis involve triggering pro-tumor inflammation and promoting immune evasion mechanisms, thereby influencing ICB administration therapeutic outcomes (Xu et al., 2020).
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