Location of CD39+ T cell sub-populations within tumours predict differential outcomes in non-small cell lung cancer

Abstract An improved mechanistic understanding of immunosuppressive pathways in NSCLC is important to develop novel diagnostic and therapeutic approaches. Here, we reveal that the prognostic significance of the rate limiting ectonucleotidases in adenosine production CD39 and CD73 requires knowledge of cell type specific expression and localisation within tumours. In a cohort of early treatment naïve NSCLC patients, high stromal expression of CD39 and CD73 predicts poor outcome. CD39 expression amongst T cells identifies CD39+CD4+ Tregs which predict poor outcome and CD39+CD103+ CTL which confer a survival benefit if high densities are observed inside of the tumour nest. Bulk RNA Seq shows that the TME of NSCLC upregulates regulatory pathways in CD4+ T cells and exhaustion in CD8+ T cells. Analysis of single-cell RNASeq datasets illustrates that CD39+CD4+ Tregs are enriched in Treg signature gene sets, and CD39+CD103+ CTL show gene signatures indicative of an exhausted cytotoxic phenotype with an upregulated expression of CXCL13. Combined knowledge of patterns of distribution and location are required to understand the prognostic impact of CD39+ T cell populations in NSCLC. This study provides an improved understanding of the spatial and functional characteristics of CD39+ T cells and illustrates their significance to patient outcome.