General introduction and thesis outline 13 1 treatment. Biomarkers with a high negative predictive value can reliably predict this lack of therapeutic benefit, thus holding paramount significance for preventing overtreatment. As described earlier, this type of biomarker not only minimizes the risk of unnecessary side effects but also serves to reduce health care costs. Moreover, it offers the possibility of providing patients with alternative treatment options at an early stage. The initial biomarker examined for its predictive potential in advanced NSCLC patients treated with PD-(L)1 blockade was the assessment of PD-L1 expression in tumor tissue. This was done due to its function in the inhibitory PD-L1/PD-1 pathway that is targeted by this treatment. Several studies have shown a positive correlation between high PD-L1 expression and improved response rates and survival13,19,20. For example, the results of the phase III KEYNOTE-024 study demonstrated that pembrolizumab led to significantly prolonged progression-free and overall survival compared to platinum-based chemotherapy in patients with PD-L1 expression levels of ≥50%13,20. Subsequently, PD‑L1 assessment via IHC received clinical approval as a predictive biomarker test. However, different studies have published conflicting results, as some patients with PD‑L1 low or PD-L1 negative tumors have also shown long-term disease control with ICB agents14–16. Furthermore, PD-L1 expression levels can vary due to factors such as interassay variability21, intratumor heterogeneity22–25 and sample characteristics including age, biopsy site, and timing26,27. Another common hurdle is obtaining sufficient tumor tissue samples for PD-L1 testing, as the tumor site is often difficult to reach and invasive procedures are needed. Tumor Mutation Burden (TMB), defined as the total number of nonsynonymous mutations per sequenced coding area of a tumor genome, has subsequently been studied as predictive biomarker for PD-(L)1 blockade monotherapy. It is thought that a higher TMB increases the likelihood of tumor neoantigen production and therefore, potential immunogenicity and the killing of cancer cells28. While TMB has shown predictive potential, no universally applicable TMB threshold has consistently demonstrated the ability to predict overall survival. Also, technical challenges have been reported due to variation across different sequencing platforms29. As PD-(L)1 blockade is thought to reinvigorate dysfunctional T cells30, the presence of tumor-infiltrating lymphocytes (TILs) has been investigated as a predictive biomarker. Although TIL density has shown predictive potential31,32, increasing evidence suggests that not all TILs are in a state to recognize and eliminate tumor cells33,34. Therefore, general TIL density is not an accurate predictive biomarker for ICB response. Previous work showed that CD8+ TILs with high PD-1 expression, referred
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