A burned-out CD8+ T-cell subset expands in the tumor microenvironment and curbs cancer immunotherapy

Tumor-infiltrating lymphocytes (TILs) are considered to be exhausted, lacking proliferative and effector functions, which impairs cancer immunity. We employed single-cell mass cytometry and tissue imaging technologies to dissect TILs in 25 resectable and 35 advanced non-small cell lung cancer (NSCLC) patients. We identified a phenotypically burn-out CD8 TIL subset (Ebo), specifically accumulated within the tumor microenvironment (TME). In contrast to exhausted T-cells, Ebo appears to be the most proliferative TIL subset. Furthermore, Ebo showed the highest expression of activation markers, but it was more apoptotic and produced less IFNg than other CD8 TIL subsets. Using a humanized patient-derived tumor xenograft model, we demonstrated that Ebo expansion occurred within the TME in a PD-pathway dependent manner. Importantly, Ebo abundance in baseline tumor tissues was associated with resistance to anti-PD therapy in NSCLC patients. Our study identified a dysfunctional TIL subset, distinct from exhausted T-cells, and implies strategies to overcome resistance in cancer immunotherapy. Overall design: There are 3 groups, 3 samples in each group, overall 9 samples analyzed