Clarke et al. used transcriptomic analysis in concert with analysis of protein expression and chromatin accessibility to characterize CD103+ resident memory T (TRM) cells in human healthy lung and lung tumors. High PD-1 expression was common on all TRM cells and PD-1+ TRM cells demonstrated clonal expansion in tumors. A TIM-3+IL-7R- TRM subset that was exclusive to tumors expressed high levels of PD-1, yet was proliferative, responded to TCR activation, and was cytotoxic, suggesting that PD-1 expression may not indicate dysfunction in TRM cells. PD-1+TIM3+ TRM cells were enriched in responders to PD-1 blockade.
High numbers of tissue-resident memory T (TRM) 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 TRM and non-TRM cells present in tumor and normal lung tissue from patients with lung cancer revealed that PD-1-expressing TRM cells in tumors were clonally expanded and enriched for transcripts linked to cell proliferation and cytotoxicity when compared with PD-1-expressing non-TRM cells. This feature was more prominent in the TRM 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(+) TRM 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, TRM cells with PD-1 expression were enriched for features suggestive of superior functionality.