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 (Tex^stem) that retain cancer-killing capacity, and terminally exhausted T cells (Tex^term) with limited function. Previously, we identified CD8 Tex^stem and Tex^term cells in malignant pleural effusions (PEs) of non-small cell lung cancer (NSCLC) and mesothelioma patients. In both cancers, increased frequency of Tex^stem 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 Tex^stem and Tex^term cells in the blood of patients with NSCLC also associated with survival. Using flow cytometry, we quantified Tex^stem and Tex^term 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 Tex^stem (3.8% vs. 9.4% of CD8 T cells, P=0.006) and Tex^term (0.3% vs. 1.1%, P=0.002). However, both subsets were significantly correlated between the two sites (Tex^stem r=0.82, P<0.001; Tex^term r=0.63, P=0.01). Higher Tex^stem 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 Tex^stem 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, Tex^term cells in the blood did not correlate with OS. Our results further support the importance of Tex^stem 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).