INTERNATIONAL CONGRESS OF
CancerGenetics
The Dual Role of PD-L1 in Gastric Cancer: Prognostic Marker and Therapeutic Target
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Mohammadamir kakaee,1,*
1. Shahid Beheshti University of Medical Sciences
- Introduction: Gastric cancer is one of the most common cancers globally, ranking fourth in incidence and second in mortality among all cancers. It is a complex and multifactorial disease involving various etiological factors such as Helicobacter pylori infection, high salt intake, smoking, and genetic predispositions.Despite advancements in treatment, including surgery and chemotherapy, the prognosis remains poor,. Programmed death-ligand 1 (PD-L1) is a protein that plays a significant role in suppressing the immune system by binding to its receptor, PD-1, on T cells. In gastric cancer, PD-L1 expression has been associated with various clinical outcomes. Studies have shown that PD-L1 is upregulated in gastric cancer tissues and is positively correlated with the presence of tumor-infiltrating immune cells (TIICs). PD-L1 expression in tumor cells and TIICs has been linked to better prognosis in some cases, particularly when co-expressed with PD-1. However, other studies have reported that high PD-L1 expression is associated with poor prognosis and advanced disease stages.
- Methods: A comprehensive literature search was conducted across three databases: PubMed, the Scientific Information Database (SID), and Web of Science. The search covered the period from 2013 to 2024 and utilized the keywords "PD-L1 marker" and "gastric cancer." In the SID database, one relevant result was identified. The PubMed search yielded a total of 189 articles. After applying the inclusion criteria, 11 articles were selected for further review. Following the removal of duplicate records, a total of 19 articles were examined in detail to assess the role of the PD-L1 marker in gastric cancer
- Results: Mechanism and Physiological Relationship Between Stomach Cancer and PD-L1 Protein Mechanism: 1. Immune Evasion: PD-L1 (Programmed Death-Ligand 1) is a protein expressed on the surface of tumor cells, including gastric cancer cells. It binds to the PD-1 receptor on T cells, leading to the inhibition of T cell activity and allowing cancer cells to evade immune detection and destruction. 2. Regulation of PD-L1 Expression: The expression of PD-L1 in gastric cancer can be regulated by various mechanisms, including genetic alterations, epigenetic modifications, and signaling pathways. For instance, the EZH2 enzyme can enhance PD-L1 stability through the deubiquitination process mediated by USP22, promoting immune evasion [Yang, 2024]. Additionally, the loss of Fructose-1,6-bisphosphatase (FBP1) can upregulate PD-L1 expression via the STAT3 pathway, further contributing to immune escape. 3. Tumor Microenvironment: PD-L1 expression is also influenced by the tumor microenvironment. Factors such as hypoxia, inflammatory cytokines, and the presence of immune cells can modulate PD-L1 levels on tumor cells, affecting the immune response. Physiological Relationship: 1. Immune Checkpoint Inhibition: The interaction between PD-1 on T cells and PD-L1 on gastric cancer cells is a critical immune checkpoint that suppresses the immune response. Blocking this interaction with immune checkpoint inhibitors (ICIs) can restore T cell activity and enhance the immune system's ability to target and destroy cancer cells. 2. Therapeutic Implications: The expression of PD-L1 in gastric cancer has significant implications for immunotherapy. High PD-L1 expression is often associated with a better response to ICIs, making it a valuable biomarker for selecting patients who may benefit from such treatments. 3. Clinical Outcomes: The relationship between PD-L1 expression and clinical outcomes in gastric cancer is complex. While some studies suggest that high PD-L1 expression correlates with better prognosis and response to therapy, others indicate that it may be associated with more aggressive disease and poorer outcomes
- Conclusion: Unlocking the Secrets of PD-L1 Prognostic Power Some studies suggest that the co-expression of PD-1 and PD-L1 in tumor cells and immune cells paints a rosy picture, hinting at a favorable prognosis. This harmonious duet could be the key to reducing mortality risk. On the other hand, patients with high PD-L1 expression accompanied by low CD8/FOXP3 ratios might experience increased survival rates. It appears that the intersection of multiple immune markers can yield more accurate survival predictions. The Shadowy Side of PD-L1 However, other findings reveal a darker tale. Elevated PD-L1 expression coupled with low densities of TILs portends a poor prognosis. This correlation suggests that PD-L1 alone may not be a reliable harbinger of fate. Furthermore, high levels of post-operative EV PD-L1 could signal a poor overall survival and recurrence-free survival. #### Taking the Pulse of Therapy Response Chemotherapy Insights The connection between PD-L1 and MSI status holds promise for predicting chemotherapy efficacy. In MSI-high tumors with PD-L1 positive, adjuvant chemotherapy demonstrates better disease-free survival compared to microsatellite-stable counterparts. This harmony could guide treatment decisions and optimize outcomes. Immunotherapy's delicate Dance PD-L1's intricate relationship with HER-2 status reveals a complex melody. Patients with tumors bearing both PD-L1 and HER-2 positive status tend to experience lower progression-free survival. This harmonious union might serve as a predictive harmonica, allowing us to anticipate both prognosis and immunotherapy efficacy. PD-L1 serves as a significant marker in gastric cancer, offering both strengths and weaknesses in its application as a prognostic and predictive tool. One of the key strengths of PD-L1 is its comprehensive prognostic value. When integrated with other immune markers, such as CD8 and FOXP3, PD-L1 enhances the accuracy of prognosis and aids in better patient stratification. This allows for a more nuanced understanding of a patient's likely disease progression, leading to more tailored treatment approaches. Additionally, PD-L1 provides therapeutic guidance by helping to identify patients who are more likely to benefit from immunotherapy and chemotherapy, thus supporting personalized treatment strategies. This makes PD-L1 a valuable tool in the context of precision medicine. However, there are notable weaknesses in using PD-L1 as a sole marker. Its prognostic value is inconsistent, as different studies report conflicting outcomes. Some research suggests that PD-L1 is associated with favorable prognoses, while others link it to poor outcomes. This inconsistency makes it difficult to rely on PD-L1 alone for accurate prognostication. Furthermore, the complex interactions between PD-L1 expression and the immune microenvironment present additional challenges. The relationship is intricate, and accurate predictive modeling often requires the integration of multiple markers rather than relying on PD-L1 in isolation. In summary, while PD-L1 has substantial strengths in enhancing prognostic accuracy and guiding therapeutic decisions, its inconsistent prognostic value and the complex interactions with the immune environment limit its effectiveness as a standalone marker.
- Keywords: Gastric cancer PD-L1 New marker
