Although immunotherapy has shown great promise in several cancer types, immunotherapy success in colorectal cancer (CRC) is mainly limited to patients whose tumours exhibit high microsatellite instability (MSI). Treatment outcomes often vary dramatically across patients, partly due to the frequencies and characteristics of different tumour infiltrating immune cells. In general, the presence of specific immune cells has been shown to be prognostic of treatment outcome. It is known that CD8+ T cells can undergo different differentiation programs, for example, to become tissue resident cells or become “exhausted” after persistent antigen exposure in the tumour microenvironment (TME), whereby they lose their functionality and express inhibitory receptors. Although relatively well known in CD8+ T cells, residency (Res) and exhaustion (Exh) programs are not well known in CD4+ T cells and largely unknown in natural killer (NK) cells.
Using single-cell RNA-seq data, we define distinct Res and Exh signatures for CRC infiltrating immune cells, including CD8+, CD4+ and NK cells. We then test these signatures in independent single cell data from tumour and normal tissue infiltrating immune cells. Additionally, we define versions of these signatures that can be used in bulk RNA-seq data from tumour samples. We use these signatures to identify tumour intrinsic mutations associated with Res and Exh in TCGA colon adenocarcinoma. Finally, we show that combinations of these signatures, in particular combinations of NK activity signatures, together with tumour-associated signatures, such as TGF-β signalling, are associated with distinct survival outcomes in patients with colon adenocarcinoma in two independent data sets.