The advent of immunotherapy has revolutionized cancer treatment, particularly through the use of immune checkpoint inhibitors (ICIs) that target PD-1/PD-L1 and CTLA-4 pathways. Despite significant advances, predicting which patients will benefit from these therapies remains a major challenge. Recent research highlights several promising biomarkers that could enhance patient selection and treatment outcomes.
Key Biomarkers in Immunotherapy
- PD-L1 Expression: PD-L1 expression is the most established biomarker for predicting response to ICIs. However, its predictive capability is limited due to variability in testing methods and cutoff values across different studies. For example, PD-L1 IHC testing can vary depending on the antibody used, leading to inconsistent results (Frontiers) (Frontiers).
- Tumor Mutational Burden (TMB): TMB measures the number of mutations within a tumor genome and has emerged as a significant predictor of response to ICIs. High TMB is associated with a greater likelihood of producing neoantigens, which can enhance the immune system’s ability to recognize and attack cancer cells (BioMed Central). Studies have shown that patients with high TMB have better outcomes when treated with PD-1/PD-L1 inhibitors (Comprehensive Cancer Information).
- Microsatellite Instability (MSI): MSI-high status, indicative of defects in DNA mismatch repair, has been linked to favorable responses to ICIs. Tumors with high MSI tend to have a higher number of neoantigens, making them more immunogenic and responsive to treatments like pembrolizumab (Comprehensive Cancer Information).
- Liquid Biopsies: Liquid biopsies offer a non-invasive method to monitor biomarkers in real-time. They can detect circulating tumor DNA (ctDNA), which provides insights into tumor dynamics and treatment response. Liquid biopsies have shown potential in supplementing traditional PD-L1 testing, particularly in breast cancer, where they can help identify patients who are more likely to respond to ICIs (Frontiers).
Emerging Biomarkers and Clinical Applications
- Clonal Neoantigens: Recent research has highlighted the importance of clonal neoantigens—neoantigens present in all cancer cells of a tumor—as predictors of response to ICIs. Tumors with high levels of clonal neoantigens are more likely to elicit a strong immune response and show better outcomes with immunotherapy (Comprehensive Cancer Information).
- CD8 and LAG-3 Expression: The presence of CD8+ T cells and the expression of LAG-3 in the tumor microenvironment are also being investigated as biomarkers. High levels of these markers have been associated with better responses to ICIs, particularly in hepatocellular carcinoma (Frontiers).
- YKL-40 Levels: Elevated plasma levels of YKL-40, a glycoprotein associated with inflammation and cancer progression, have been linked to poorer outcomes in patients receiving ICIs. This biomarker could help identify patients who might benefit from additional therapeutic strategies (Frontiers).
Challenges and Future Directions
While these biomarkers show promise, their integration into clinical practice faces several challenges. Variability in testing methods, the complexity of tumor biology, and the need for large-scale validation studies are significant hurdles. Combining multiple biomarkers into a comprehensive predictive model may offer a more accurate assessment of patient response to immunotherapy (Comprehensive Cancer Information).
Ongoing research is focused on refining these biomarkers and exploring new ones to enhance the precision of immunotherapy. Future studies will likely focus on integrating genomic, proteomic, and immunological data to develop robust, multifaceted biomarker profiles (Frontiers).
References
- Liquid biopsy biomarkers to guide immunotherapy in breast cancer. Frontiers in Immunology. 2023. Link
- Predictive biomarkers for cancer immunotherapy with immune checkpoint inhibitors. Biomarker Research. 2023. Link
- A New Biomarker for Response to Checkpoint Inhibitors. National Cancer Institute. 2024. Link
