Chapter 2 - Commentary by Anagnostou V and Luke JJ 281 A Commentary Summary Analysis of tumor-infiltrating lymphocyte (TIL) functional states, particularly tumor-reactive PD-1T TILs, within specific spatial context, can serve as a biologically informed predictive marker of immunotherapy that may be superior to standard clinical biomarkers. High-plex quantitative immune cell phenotyping within their spatial context has tremendous potential in immuno-oncology. In this issue of Clinical Cancer Research, Hummelink and colleagues report on programmed cell death protein 1 (PD-1T) TILs, a tumor-reactive tumor-infiltrating T lymphocyte (TIL) pool, as a predictive biomarker for immunotherapy in non–small cell lung cancer1 (NSCLC). PD-1T TILs represent an intratumoral CD8+ T-cell population with high PD-1 expression, distinct transcriptional profiles, and increased tumor recognition capacity2. This subset of PD-1+ tumor-infiltrating T cells is preferentially recruited in tertiary lymphoid structures (TLS) and can be identified by bright PD-1 expression that can be digitally quantified and distinguished from other PD-1+ cells1,2. Hummelink and colleagues report their findings on the predictive accuracy of PD-1T TILs in the context of immune checkpoint inhibitor (ICI) therapy for patients with NSCLC receiving nivolumab or pembrolizumab. Following a digital workflow for PD-1T TIL quantification in formalin-fixed paraffin-embedded tissue, the authors evaluated the association of PD-1T TIL density with clinical outcomes, focusing on disease control at 6 months (a surrogate endpoint also known as durable clinical benefit3) as their primary endpoint. The predictive accuracy of PD-1T TIL density (AUC ROC, 0.72–0.79) was superior to that of programmed death-ligand 1 (PD-L1) TPS score, commonly used in NSCLC to identify tumors more likely to regress with ICIs (AUC ROC, 0.58). Notably, the predictive nature of PD-1T TILs may be enhanced for determining long-term clinical outcome and sustained clinical response past 6 months (ROC AUC, 0.79–0.89 for prediction of disease control at 12 months). As PD1T TILs were predominantly found in TLSs1,2 and the role of mature TLS in antitumor immune responses in the context of immune checkpoint blockade4, the authors investigated the incremental value of assessing PD-1T TILs over the number of TLS within the analyzed tumors; these analyses showed that the predictive value of PD1T TILs was not driven by TLS density alone (ROC AUC for the latter 0.62). Taken together, these findings build on the previously reported role of this functionally distinct subset of CD8+ intratumoral T cells2 and support PD-1T TILs as a putative determinant of response to immune checkpoint blockade and suggest that prospective validation in larger cohorts should be prioritized.
RkJQdWJsaXNoZXIy MTk4NDMw