Only one in four lung cancer patients survive beyond 5 years, making lung cancer the biggest cause of cancer deaths globally, with over 1.8 M deaths worldwide /yr. While immunotherapy has led to major improvements in the quality of life and survival of lung cancer patients, only 20% of patients respond to these treatments. Dissecting how immune pressure imposed by the tumour microenvironment can impact tumour evolution is essential to understanding mechanisms of immune evasion and developing better therapeutic strategies.
Tissue-resident memory T cells (TRM) provide immune defence against local infection and can inhibit cancer progression. However, it is unclear to what extent chronic inflammation impacts TRM activation and whether pre-existing TRM influence tumour evolution in humans. We performed deep profiling of healthy lungs and lung cancers in never-smokers (NS) and ever-smokers (ES), finding evidence of enhanced TRM immunosurveillance in ES lungs. In preclinical models, tumour-specific or bystander TRM present prior to tumour onset boosted immune cell recruitment, causing tumour immune evasion through loss of MHC Class I protein expression, and resistance to immune checkpoint inhibitors. In humans, only tumours arising in ES patients underwent clonal immune escape, suggesting that the timing of immune pressure exerted by TRM is a critical factor in the evolution of tumour immune evasion. Tumours grown in T cell quiescent NS lungs displayed little evidence of immune evasion. These data demonstrate that enhanced TRM activity prior to tumour development shapes the evolution of tumour immunogenicity and can impact immunotherapy outcomes. Furthermore, through spatial proteomic and transcriptomic analysis of surgically-resected non-small cell lung cancer, we identified clusters of TRM and myeloid cells that were associated with better survival only when present in the tumour core, indicating TRM cells act in concert with other immune subsets in controlling tumour growth and evolution.