Circulating stem-like exhausted CD8 T cells point to better outcomes in lung cancer: a brief report.

Anti-cancer T cells exhibit a spectrum of functional abilities and exhaustion levels and can be broadly categorized as stem-like exhausted T cells (Texstem) that retain cancer-killing capacity, and terminally exhausted T cells (Texterm) with limited function. Previously, we identified CD8 Texstem and Texterm cells in malignant pleural effusions (PEs) of non-small cell lung cancer (NSCLC) and mesothelioma patients. In both cancers, increased frequency of Texstem cells was associated with improved overall survival (OS). However, not all cancer patients develop PE, and sampling of PE is invasive, with associated risks. In this study we sought to determine if Texstem and Texterm cells in the blood of patients with NSCLC also associated with survival. Using flow cytometry, we quantified Texstem and Texterm in blood samples from 30 patients with advanced NSCLC and assessed their correlation with OS. In half of these cases, we also analyzed matched PE samples for comparison. Compared to PE, peripheral blood had a lower frequency of Texstem (3.8% vs. 9.4% of CD8 T cells, P=0.006) and Texterm (0.3% vs. 1.1%, P=0.002). However, both subsets were significantly correlated between the two sites (Texstem r=0.82, P<0.001; Texterm r=0.63, P=0.01). Higher Texstem cell frequency in the blood was associated with improved survival after adjusting for potentially prognostic patient and tumor related factors. When stratified into high and low groups based on the median, higher Texstem cells levels correlated with better OS [hazard ratio (HR) 0.16, 95% confidence interval (CI): 0.03-0.10, P=0.048]. As shown previously in PE, Texterm cells in the blood did not correlate with OS. Our results further support the importance of Texstem in the anti-cancer immune response and provide useful evidence for the utility of peripheral blood sampling for future studies examining exhausted T cells (Tex).