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.
Author Info: (1) La Jolla Institute for Immunology, La Jolla, CA. National Institute for Health Research and Cancer Research UK Southampton Experimental Cancer Medicine Center, National Institu
Author Info: (1) La Jolla Institute for Immunology, La Jolla, CA. National Institute for Health Research and Cancer Research UK Southampton Experimental Cancer Medicine Center, National Institute for Health Research Southampton Biomedical Research Center, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK. (2) La Jolla Institute for Immunology, La Jolla, CA. (3) La Jolla Institute for Immunology, La Jolla, CA. (4) La Jolla Institute for Immunology, La Jolla, CA. (5) La Jolla Institute for Immunology, La Jolla, CA. (6) National Institute for Health Research and Cancer Research UK Southampton Experimental Cancer Medicine Center, National Institute for Health Research Southampton Biomedical Research Center, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK. (7) National Institute for Health Research and Cancer Research UK Southampton Experimental Cancer Medicine Center, National Institute for Health Research Southampton Biomedical Research Center, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK. Southampton University Hospitals National Health Service Foundation Trust, Southampton, UK. (8) La Jolla Institute for Immunology, La Jolla, CA. (9) National Institute for Health Research and Cancer Research UK Southampton Experimental Cancer Medicine Center, National Institute for Health Research Southampton Biomedical Research Center, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK. Department of Otolaryngology, Poole Hospital National Health Service Foundation Trust, Poole, Dorset, UK. (10) Southampton University Hospitals National Health Service Foundation Trust, Southampton, UK. Clinical and Experimental Sciences, National Institute for Health Research Southampton, Respiratory Biomedical Research Unit, University of Southampton, Faculty of Medicine, Southampton, UK. (11) National Institute for Health Research and Cancer Research UK Southampton Experimental Cancer Medicine Center, National Institute for Health Research Southampton Biomedical Research Center, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK. (12) National Institute for Health Research and Cancer Research UK Southampton Experimental Cancer Medicine Center, National Institute for Health Research Southampton Biomedical Research Center, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK. (13) La Jolla Institute for Immunology, La Jolla, CA. (14) Southampton University Hospitals National Health Service Foundation Trust, Southampton, UK. (15) Southampton University Hospitals National Health Service Foundation Trust, Southampton, UK. (16) La Jolla Institute for Immunology, La Jolla, CA. (17) National Institute for Health Research and Cancer Research UK Southampton Experimental Cancer Medicine Center, National Institute for Health Research Southampton Biomedical Research Center, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK. (18) La Jolla Institute for Immunology, La Jolla, CA. (19) Clinical and Experimental Sciences, National Institute for Health Research Southampton, Respiratory Biomedical Research Unit, University of Southampton, Faculty of Medicine, Southampton, UK. (20) Clinical and Experimental Sciences, National Institute for Health Research Southampton, Respiratory Biomedical Research Unit, University of Southampton, Faculty of Medicine, Southampton, UK. (21) La Jolla Institute for Immunology, La Jolla, CA. (22) National Institute for Health Research and Cancer Research UK Southampton Experimental Cancer Medicine Center, National Institute for Health Research Southampton Biomedical Research Center, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK C.H.Ottensmeier@soton.ac.uk. (23) La Jolla Institute for Immunology, La Jolla, CA vijay@lji.org. Clinical and Experimental Sciences, National Institute for Health Research Southampton, Respiratory Biomedical Research Unit, University of Southampton, Faculty of Medicine, Southampton, UK. Department of Medicine, University of California San Diego, La Jolla, CA.
