Single-cell transcriptomic analysis of tissue-resident memory T cells in human lung cancer

High numbers of tissue-resident memory T (T_RM) cells are associated with better clinical outcomes in cancer patients. However, the molecular characteristics that drive their efficient immune response to tumors are poorly understood. Here, single-cell and bulk transcriptomic analysis of T_RM and non-T_RM cells present in tumor and normal lung tissue from patients with lung cancer revealed that PD-1-expressing T_RM cells in tumors were clonally expanded and enriched for transcripts linked to cell proliferation and cytotoxicity when compared with PD-1-expressing non-T_RM cells. This feature was more prominent in the T_RM cell subset coexpressing PD-1 and TIM-3, and it was validated by functional assays ex vivo and also reflected in their chromatin accessibility profile. This PD-1⁺TIM-3⁺ T_RM cell subset was enriched in responders to PD-1 inhibitors and in tumors with a greater magnitude of CTL responses. These data highlight that not all CTLs expressing PD-1 are dysfunctional; on the contrary, T_RM cells with PD-1 expression were enriched for features suggestive of superior functionality.