In-person Oral Presentation 34th Lorne Cancer Conference 2022

Early immune pressure imposed by tissue resident memory T cells sculpts tumour evolution in non-small cell lung cancer (#48)

Clare Weeden 1 , Vel Gayevskiy 1 , Claire Marceaux 1 , Allison Clatch 2 , Susan Christo 2 , Charis Teh 1 , Terry Speed 1 , Charles Swanton 3 , Laura McKay 2 , Claire Gordon 2 , Daniel Gray 1 , Marie-Liesse Asselin-Labat 1
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. Peter Doherty Institute, Melbourne
  3. The Crick Institute, London

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 how the immune pressure exerted by TRM affects developing tumours in humans. We performed deep profiling of lung cancers arising in never-smokers (NS) and ever-smokers (ES), finding evidence of enhanced TRM immunosurveillance in ES lung. Only tumours arising in ES patients underwent clonal immune escape, even when evaluating cancers with similar tumour mutational burden to NS patients, 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 and had fewer neoantigens with low diversity, paradoxically making them amenable to treatment with agonist of the costimulatory molecule, ICOS. These data demonstrate local environmental insults enhance TRM immunosurveillance of human tissue, shape the evolution of tumour immunogenicity and that this interplay informs effective immunotherapeutic modalities.