Chapter 7 236 Tumor specific CD8+ T cells possess the capacity to recognize and eliminate cancer cells. However, they are often functionally impaired in the tumor microenvironment (TME), for instance via the PD-1/PD-L1 signaling pathway. Therapeutic blockade of this pathway has the potential to reinvigorate dysfunctional T cells, which are characterized by high expression of inhibitory receptors such as PD-1, CTLA-4 and TIM-3, and secrete CXCL13. Furthermore, they show an increased capacity for tumor recognition5–7. We hypothesized that a new biomarker could be developed by assessing such direct effectors of the anti-tumor immune response. In chapter 2 we validated PD-1T tumor infiltrating lymphocytes (TILs), a dysfunctional CD8+ TIL subpopulation7, as a novel biomarker for prediction of treatment benefit to PD-1 blockade in NSCLC. Importantly, the high NPV of this biomarker may allow for reliable identification of patients unlikely to benefit from PD‑1 blockade. Furthermore, PD-1T TILs have been found across cancer types and have shown similar predictive potential8, making it interesting to test this biomarker in other cancer types for which PD-1 blockade monotherapy is available. Unlike PD-1T TILs, which serve as a direct indicator of an effective tumor-specific T cell response, the commonly used biomarker in routine clinical practice, PD-L1, is primarily considered a surrogate marker. In essence, PD-L1, expressed on the surface of tumor cells, binds to the PD-1 receptor on activated T cells, leading to an inhibitory effect. PD-(L)1 blocking agents target this interaction, thereby enhancing the ‘preexisting’ anti-tumor immune activity. Nevertheless, a subset of patients with low PD-L1 expression or PD-L1 negative tumors can still show long-term disease control when treated with agents targeting the PD-1/PD-L1 axis1,9. Importantly, in chapter 2, we demonstrated that PD-1T TILs outperformed the PD-L1 tumor proportion score (TPS), and the combination of both did not improve predictive accuracy. This suggests that PD-1T TIL scoring has the potential to serve as a biomarker for response to PD-1 blockade monotherapy, irrespective of PD-L1 status. Further, in chapter 2, we describe that PD-1T TILs predominantly reside in tertiary lymphoid structures (TLS)7. TLS are characterized by the presence of a central cluster of B cells surrounded by a border zone of T cells. They tend to form in chronic inflammation and in various cancer types, including NSCLC10–12. TLS have been associated with favorable responses and improved survival outcomes following ICB treatment8,13–16. We observed that using TLS as a single biomarker resulted in lower predictive accuracy compared to PD-1T TILs. It remains to be investigated whether factors such as spatial heterogeneity of TLS in peri- and intratumoral regions may account for this outcome. Our findings revealed that the frequency of TLS did not significantly differ between PD-1T high (≥90 per mm2) and PD-1T low (<90 per
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