Tumour-associated tissue-resident memory T (TRM) cells and exhausted T cells are clonally and developmentally distinct populations

CD8+ T cells serve as a key weapon in the therapeutic armamentarium against cancer. While CD8+ CD103+ T cells with a tissue-resident memory (TRM) phenotype have been favourably correlated with patient prognoses1-6, the tumour microenvironment comprises dysfunctional exhausted T (TEX) cells that exhibit a myriad of TRM-like features, leading to conflation of these cell types. Here, we deconvolute TRM and TEX cells within the intratumoural CD8+ CD103+ T cell pool across human cancers, ascribing markers and gene signatures that distinguish these CD8+ populations and enable their functional distinction. We found that while TRM cells exhibit superior functionality and are associated with long-term survival post tumour resection, TEX cells are associated with responsiveness to immune checkpoint blockade. Importantly, we show that tumour-associated TEX and TRM cells are clonally and developmentally distinct populations, with the latter predominantly comprised of low affinity and tumour-independent bystanders. Tumour-specific TRM cells may form in circumstances where specific tumour antigens are lost or inaccessible, and these TRM cells can be pushed towards exhaustion when cognate antigen is re-encountered. Thus, chronic T cell receptor signalling within tumours is the key distinction between tumour-associated TRM and TEX cells. Therefore, the most fruitful approaches to utilise TRM cells in anti-tumour therapies are likely embedded in the repurposing of tumour-independent TRM cells already present within tumours. Overall design: Breast tissue from women with breast cancer and blood from healthy women was sampled and CD3+ cells sequenced.