International Journal of Clinical Case Reports 2024, Vol.14, No.4, 189-201 http://medscipublisher.com/index.php/ijccr 193 3.1 Composition of immune cells in the tumor microenvironment The TME of RCC is characterized by the presence of a variety of immune cells, including cytotoxic T cells (CD8+), regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and dendritic cells. RCC has been shown to be one of the most immune-infiltrated tumors across different cancers, with tumor-infiltrating lymphocytes (TILs) being a common feature (Diaz-Montero et al., 2020). However, despite the presence of these immune cells, many fail to mount an effective anti-tumor response due to the immunosuppressive signals present within the TME (Chen, 2024). Tregs and MDSCs, which inhibit cytotoxic T cell activity, are frequently found in RCC tumors and contribute to the suppression of the immune response. TAMs, particularly those with an M2 phenotype, also play an immunosuppressive role, promoting tumor growth and survival by inhibiting the activity of effector T cells. Conversely, CD8+ T cells, which are responsible for killing tumor cells, often exhibit exhaustion markers like PD-1, rendering them ineffective against the tumor (Rappold et al., 2021). This complex interplay of immune cell populations within the TME is a significant determinant of how well a patient responds to ICB therapy. 3.2 Correlation between PD-L1 expression and the efficacy of immune checkpoint blockade PD-L1 (programmed death-ligand 1) expression in tumor cells has been widely studied as a potential biomarker for predicting the efficacy of PD-1/PD-L1 blockade therapies in RCC. PD-L1, when expressed on the surface of tumor cells or immune cells within the TME, binds to the PD-1 receptor on T cells, leading to their exhaustion and reduced anti-tumor activity. Therefore, high PD-L1 expression has been hypothesized to indicate a greater likelihood of response to PD-1/PD-L1 inhibitors, such as nivolumab. However, the relationship between PD-L1 expression and treatment outcomes is complex. While several studies have demonstrated that high PD-L1 expression correlates with better responses to PD-1 blockade, there are also cases where patients with low or no PD-L1 expression still respond to treatment (Vuong et al., 2019). This inconsistency suggests that PD-L1 expression alone may not be a sufficient predictor of response and that other factors, such as the composition of the immune infiltrate and the overall immune landscape of the TME, play crucial roles in determining the efficacy of ICB therapy (Xu et al., 2020). 3.3 Other biomarkers potentially affecting efficacy Beyond PD-L1 expression, several other biomarkers are being investigated for their potential to predict response to immune checkpoint blockade in RCC. Tumor mutational burden (TMB) refers to the total number of mutations present within a tumor's genome. High TMB has been associated with better responses to ICB in several cancer types, including RCC, as tumors with more mutations are thought to produce more neoantigens, which can be recognized by the immune system (Rappold et al., 2021). Microsatellite instability (MSI) is another biomarker that has been linked to better responses to ICB. MSI occurs when the DNA mismatch repair system is deficient, leading to a high mutation rate. While MSI is less common in RCC compared to other cancers such as colorectal cancer, its presence could still indicate a higher likelihood of response to ICB therapy. Other emerging biomarkers include gene expression signatures related to immune activation, such as interferon-gamma signatures, and specific genetic alterations like mutations in the PBRM1 gene, which have been associated with enhanced responses to PD-1 blockade in RCC (Bi et al., 2021). The identification and validation of these biomarkers are critical for developing personalized approaches to ICB therapy, ensuring that the right patients receive the most effective treatments. 4 Application of Immune Checkpoint Blockade Therapy in Renal Cell Carcinoma Immune checkpoint blockade (ICB) therapy has transformed the treatment landscape for metastatic renal cell carcinoma (mRCC). These therapies target key immune regulatory pathways that tumors exploit to evade immune detection and destruction.
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