Summary and future perspectives 241 7 To facilitate the translation of the PD-1T TILs biomarker into clinical practice, chapter 4 aimed to develop a robust method suitable for use in routine clinical diagnostics. Using the Nanostring nCounter platform, we developed an mRNA signature that reflects a tumor’s PD-1T TIL status and predicts the clinical outcome of NSCLC patients treated with PD-1 blockade monotherapy. The PD-1T gene expression signature showed equally high sensitivity and NPV as the digital image analysisbased IHC quantification of PD-1T TILs. This mRNA signature enables accurate identification of patients with long-term benefit (DC 12m) from PD-1 blockade monotherapy as well as those with a low chance of benefitting from it. The PD-1T signature successfully matches the dysfunctional expression profile of PD-1T TILs, as it includes the co-inhibitory signaling molecules LAG3 and CTLA4. High expression of these genes, alongside PD-1, characterizes T cells in a late stage of differentiation marked by a loss of proliferative capacity and impaired cytotoxic function. This impairment is largely attributable to chronic tumor antigen stimulation within the TME7,50. Importantly, it is noteworthy that all of these markers have been correlated to tumor reactivity7,36. Interestingly, another gene in the PD-1T signature is CXCL13, a chemokine constitutively expressed and secreted by PD-1T TILs. CXCL13 serves as a B cell attractant, contributing to the formation and maintenance of TLS. PD-1highCXCL13+ T cells predominantly localize in TLS7. A recent study has established a correlation between CXCL13+CD8+ T cells and favorable responses to ICB51, underscoring the robustness of CXCL13 as a marker for tumor-reactive T cells and as a predictive biomarker. The PD-1T signature also includes genes related to interferon signaling (IFIT2, OAS1, STAT1), antigen presentation (TAP1) and angiogenesis (HEY1) as well as the cytokine IL6 and the well known co-inhibitory molecule CD274 (i.e. PD-L1). Collectively, these PD-1T signature genes characterize both a pre-existing adaptive immune response and the immunosuppressive stimuli associated with T cell dysfunction52,53. As mentioned earlier, it is thought that PD-1 blockade therapy can reinvigorate these dysfunctional T cells. We can conclude that the digital-image based IHC method can reliably be replaced by a matching gene expression signature. Since we developed the PD-1T signature on the Nanostring nCounter platform, a well-established industry-standard technology, the biomarker is now more suitable for implementation. Importantly, chapter 4 illustrates that the approach used has the potential to pave the way for the integration of other expression-level-based biomarkers into routine clinical diagnostics. These biomarkers can play an important role in supporting shared decision-making for therapeutic strategies.
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