Cancer Genetics and Epigenetics 2024, Vol.12, No.6, 306-316 http://medscipublisher.com/index.php/cge 308 2023). The promising results from these trials provide a strong rationale for the continued investigation and use of ICIs in the treatment of TNBC. Figure 1 Schematic diagram of immune checkpoint blockade (Adopted from Yi et al., 2021) Image caption: MHC generally presents antigen on the surface of cancer cells for recognition by CD8+ T cells via their TCR. CTLA4, as a negative regulator, is homologous to the T cell co-stimulatory protein CD28, both of which bind to CD80 and CD86 on the surface of cancer cell but with different affinity. Overall, CTLA4 has a much higher affinity than CD28 to CD80/CD86. PD1 is expressed on T lymphocyte surface. The binding of PD1 on the T cell with PDL1 functions to suppress signals downstream of TCR activation, leading to apoptosis of the CTL. Antibodies (anti-CTLA4, anti-PD1, anti-PDL1) inhibit these checkpoint targeting proteins to restore the activity of T cells and kill cancer cells. MHC, major histocompatibility complex; TCR, T cell receptor; Ag, antigen (Adopted from Yi et al., 2021) 3 Predictive Markers for ICI Efficacy in TNBC 3.1 PD-L1 expression levels PD-L1 expression has emerged as a critical predictor of the efficacy of immune checkpoint inhibitors (ICIs) in triple-negative breast cancer (TNBC). Studies have shown that high PD-L1 expression is associated with better clinical outcomes, including improved objective response rates (ORR), progression-free survival (PFS), and overall survival (OS) in patients treated with ICIs (Qi et al., 2022; Khan et al., 2023). For instance, a meta-analysis demonstrated that PD-L1 positive TNBC patients had significantly better OS and PFS when treated with ICIs compared to PD-L1 negative patients (Qi et al., 2022). However, the predictive value of PD-L1 expression is not without limitations. Negative results from recent phase III trials, such as IMPassion131 and IMPassion132, have raised questions about the consistency of PD-L1 as a biomarker. Additionally, the variability in PD-L1 testing methods and cut-off values for positivity further complicates its utility as a universal predictive marker (Khan et al., 2023). 3.2 Tumor mutational burden (TMB) Tumor mutational burden (TMB) is another potential biomarker for predicting the efficacy of immunotherapy in TNBC. High TMB is generally associated with increased neoantigen load, which can enhance the immune system's ability to recognize and attack tumor cells. Studies have shown that high TMB correlates with better responses to ICIs in TNBC (Karn et al., 2020; Karn et al., 2022). For example, in the GeparNuevo study, high TMB was associated with increased pathological complete response (pCR) rates in patients receiving neoadjuvant chemo-ICB2. Interestingly, some data suggest that even TNBC patients with low TMB may benefit from ICI therapy, indicating that TMB alone may not be sufficient to predict response and should be considered alongside other biomarkers (Karn et al., 2022). 3.3 Other potential biomarkers Microsatellite instability (MSI) is a condition of genetic hypermutability that results from impaired DNA mismatch repair. While MSI is a well-established biomarker in other cancers, its role in TNBC is less clear.
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