Chapter 2 28 Introduction Immune checkpoint blockade (ICB) targeting the programmed cell death-1 (PD-1)/PD-ligand 1 (PD-L1) pathway has dramatically changed the treatment of advanced stage non-small cell lung cancer (NSCLC) patients. Significant improvement in survival, quality of life and a favorable safety profile compared to chemotherapy has led to the rapid and broad clinical implementation of this treatment modality1–6. However, approximately 60 to 70% of patients progress within 6 months after treatment initiation3,5,6. Hence, predictive biomarkers are needed, in particular to identify patients that are less likely to benefit to reduce overtreatment. In analogy to molecular biomarkers that have been used for identification of patients with targetable oncogenes7, it has been assumed that PD-L1 expression in tumors could predict benefit of anti-PD-1/PD-L1 therapy. Previous studies indeed have shown that pretreatment stratification based on high expression of PD-L1 can identify patient subgroups with improved response rates and survival1,2,8, leading to the approval of PD-L1 testing for newly diagnosed advanced NSCLC. However, PD-L1 is not a perfect biomarker since multiple studies have shown conflicting results with regard to its predictive potential3,5,6. As PD-1/PD-L1 blockade is thought to reactivate dysfunctional T cells9, an alternative strategy may be to develop biomarkers that reflect the capacity of a tumor to mount an anti-tumor immune response. We previously showed that the presence of a specific CD8+ tumor-infiltrating lymphocyte (TIL) subpopulation, termed PD-1T TILs, correlated with response and survival in a small cohort of NSCLC patients treated with PD-1 blockade10. PD-1T TILs are a subset of PD-1+ T cells characterized by high, tumor-associated expression levels of PD-1, and are transcriptionally and functionally distinct from other TIL populations with lower or no PD-1 expression. Importantly, PD-1T TILs show high tumor reactivity10 consistent with subsequent work in other tumor types demonstrating that the capacity for tumor recognition is strongly enriched in the dysfunctional T cell population that expresses high levels of PD-111,12. Moreover, tumor infiltration by PD-1T lymphocytes was recently associated with immunological response to PD-1 blockade in a number of other tumor types13. Finally, PD-1T TILs predominantly localize in tertiary lymphoid structures (TLS)10, which have been correlated with clinical and immunological response to ICB in other cancer types13–16. Collectively, these observations suggest that the presence of PD-1T TILs in a tumor may indicate that a tumor-specific T cell response has been mounted, and thereby represent
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