Flash Talk & Poster Presentation 32nd Lorne Cancer 2020

Deep profiling by mass cytometry reveals differing T cell activation in ever- and never-smoker lung cancer (#103)

Clare Weeden 1 , Marie Trussart 1 , Charis Teh 1 , Andrew Mitchell 2 , Tracy Leong 3 , Daniel Steinfort 4 , Louis Irving 4 , Terry Speed 1 , Daniel Gray 1 , Marie-Liesse Asselin-Labat 1
  1. The Walter and Eliza Hall Institute, Parkville, VIC, Australia
  2. Department of Chemical Engineering, University of Melbourne, Melbourne
  3. Respiratory and Sleep Medicine, Austin Health, Melbourne
  4. The Royal Melbourne Hospital, Parkville, VIC, Australia

Inhibiting immune checkpoint molecules – including programmed cell death protein (PD-1) and cytotoxic T-lymphocyte-associated-protein 4 (CTLA-4) – can induce T cell-mediated killing of cancer cells and results in significant clinical responses in ~20% of non-small-cell lung cancer patients.  However, never-smokers with lung cancer, who currently comprise 20% of lung cancer cases in Australia, typically respond poorly to checkpoint immunotherapy. Literature suggests that tumour cell intrinsic factors – including lower PDL1 expression by tumour cells and lower tumour mutational burden – account for reduced sensitivity to checkpoint inhibition. Yet tumour cell extrinsic factors, including immune parameters, are yet to be formally explored. To this end, we profiled 10 never-smoker and 10 ever-smoker patient lung and matched lung tumours with mass cytometry to explore the effects of smoking on resident memory T cells (TRM) in the human lung, and how this impacts immune infiltrate in tumours. We found lower co-stimulatory marker expression on CD4+ TRM in never-smoker lung tissue and accordingly less CD8+ TRM and resident CD4+ T regulatory cells compared to ever-smokers. In tumour tissue, infiltrating CD4+ and CD8+ TRM had less co-stimulatory and co-inhibitory (including PD-1 and CTLA4) marker expression in never-smokers. This data suggests less T cell activation in the normal lung and resultant lung tumour in never-smokers with lung cancer. Tumour cells isolated from never-smokers expressed either MHC Class I and/or MHC Class II, whereas tumours that had lost both MHC molecules were only detected in ever-smokers – potentially reflecting an outcome of differing levels of immune-surveillance during tumour development. Collectively, our data suggests that a lack of initial T cell response to tumours is a contributing factor to the inherent resistance of never-smoker patients to anti-PD1 or anti-CTLA4 therapy. We are currently focused on instead targeting co-stimulatory molecules on tumour-infiltrating T cells in never-smoker lung cancer. Our study suggests that individualized strategies will be necessary for the successful treatment of ever- and never-smoker lung cancer with immunotherapies.