Weeden et al. found higher levels of CD8+ resident memory T cells (Trm) in the healthy lungs of ever-smokers (ES) than in those of never-smokers (NS). These Trm in ES were activated earlier in progression from non-malignant to early- and late-stage cancer. Mouse lung cancer models showed that pre-existing Trm cells, independent of Ag specificity, increased T cell recruitment and activation in tumors, leading to early immune evasion and resistance to checkpoint blockade. Human lung cancer datasets confirmed these data, suggesting the “soil” in which tumors arise and the timing of immune pressure impact tumor evolution.
Contributed by Maartje Wouters
ABSTRACT: Tissue-resident memory T (T(RM)) cells provide immune defense against local infection and can inhibit cancer progression. However, it is unclear to what extent chronic inflammation impacts T(RM) activation and whether T(RM) cells existing in tissues before tumor onset influence cancer evolution in humans. We performed deep profiling of healthy lungs and lung cancers in never-smokers (NSs) and ever-smokers (ESs), finding evidence of enhanced immunosurveillance by cells with a T(RM)-like phenotype in ES lungs. In preclinical models, tumor-specific or bystander T(RM)-like cells present prior to tumor onset boosted immune cell recruitment, causing tumor immune evasion through loss of MHC class I protein expression and resistance to immune checkpoint inhibitors. In humans, only tumors arising in ES patients underwent clonal immune evasion, unrelated to tobacco-associated mutagenic signatures or oncogenic drivers. These data demonstrate that enhanced T(RM)-like activity prior to tumor development shapes the evolution of tumor immunogenicity and can impact immunotherapy outcomes.
Author Info: (1) Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, the University of Melbourne, Park
Author Info: (1) Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, the University of Melbourne, Parkville, VIC, Australia. (2) Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, the University of Melbourne, Parkville, VIC, Australia. (3) Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, the University of Melbourne, Parkville, VIC, Australia. (4) Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. (5) Immunology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. (6) Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. (7) Advanced Technology and Biology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. (8) Department of Microbiology and Immunology, the University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC, Australia. (9) Department of Microbiology and Immunology, the University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC, Australia. (10) Immunology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, the University of Melbourne, Parkville, VIC, Australia. (11) Materials Characterisation and Fabrication Platform, Department of Chemical Engineering, the University of Melbourne, Parkville, VIC, Australia. (12) Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. (13) Immunology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, the University of Melbourne, Parkville, VIC, Australia. (14) Department of Microbiology and Immunology, the University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC, Australia. (15) ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, the University of Melbourne, Parkville, VIC, Australia. (16) ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, the University of Melbourne, Parkville, VIC, Australia. (17) Department of Surgery, University of Melbourne, Parkville, VIC, Australia; Liver and Intestinal Transplant Unit, Austin Health, Heidelberg, VIC, Australia; Department of Cardiothoracic Surgery, Austin Health, Heidelberg, VIC, Australia. (18) Department of Surgery, University of Melbourne, Parkville, VIC, Australia; Liver and Intestinal Transplant Unit, Austin Health, Heidelberg, VIC, Australia. (19) DonateLife Victoria, Carlton, VIC, Australia; Department of Intensive Care Medicine, Melbourne Health, Melbourne, VIC, Australia. (20) Department of Surgery, University of Melbourne, Parkville, VIC, Australia; The Royal Melbourne Hospital, Parkville, VIC, Australia. (21) Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, the University of Melbourne, Parkville, VIC, Australia; Department of Respiratory and Sleep Medicine, Austin Health, Heidelberg, VIC, Australia. (22) Department of Medicine, the University of Melbourne, Parkville, VIC, Australia; The Royal Melbourne Hospital, Parkville, VIC, Australia. (23) Department of Medicine, the University of Melbourne, Parkville, VIC, Australia; The Royal Melbourne Hospital, Parkville, VIC, Australia. (24) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Cancer Evolution and Genome Instability Laboratory, Francis Crick Institute, London, UK; Department of Oncology, University College London Hospitals, London, UK. (25) Department of Microbiology and Immunology, the University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC, Australia; Department of Infectious Diseases, Austin Health, Heidelberg, VIC, Australia; North Eastern Public Health Unit, Austin Health, Heidelberg, VIC, Australia. (26) Department of Microbiology and Immunology, the University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC, Australia. (27) Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; School of Mathematics and Statistics, the University of Melbourne, Parkville, VIC, Australia. (28) Immunology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, the University of Melbourne, Parkville, VIC, Australia. Electronic address: dgray@wehi.edu.au. (29) Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, the University of Melbourne, Parkville, VIC, Australia. Electronic address: labat@wehi.edu.au.
