PO-401 Tumour stem cell characteristics are negatively associated with anti-cancer immunity in diverse solid cancers

Abstract

IntroductionThe majority of clinical responses to immunotherapies appear to be restricted to tumours displaying a pre-existing T cell-infiltrated tumour microenvironment. Consequently, understanding the molecular mechanisms leading to a T cell-poor microenvironment will be crucial for the development of novel treatments to increase the number of patients benefiting from immunotherapy. Increasing evidence has suggested that tumours are organised in a hierarchical structure of phenotypically heterogeneous cell populations. Cancer stem cells (CSCs) are at the top of this tumour cell hierarchy and sustain the long-term maintenance of neoplasms. The ability of CSCs, as well as physiological stem cells, like embryonic stem cells and mesenchymal stem cells, to resist immune-mediated destruction is unrivalled by more differentiated cells. Despite this, the potential impact of a cancer stem-like tumour phenotype on the ability to drive immune exclusion and avoid immune rejection has not been systematically explored.Material and methodsWe calculated an RNA-based metric of stemness for >8000 TCGA solid tumour samples. We assessed the association of this metric with transcriptomic signatures of immune cell infiltration and other genomic, transcriptomic, and clinical parameters.Results and discussionsTumour stemness varied strongly across cancers and negatively associated with patient survival both within and across cancers. We found that high stemness tumours show reduced inferred infiltration of multiple immune cell types, particularly of anti-tumour effector cells such as CD8 +T cells, B-cells, and NK cells. Within well-defined cancer molecular subtypes, we observed recurrent negative associations between stemness and immunity. We also detect negative correlations between immunity and defined stem cell regulatory pathways that reflect the activity of specific stemness transcription factors. Screening for potential stemness associated axes of immunosuppression, we found that enrichment of extracellular matrix organisation process could be a possibly mechanism of stemness-immune interference. Using published data from clinical trials of immune checkpoint blockade therapy, we showed that tumour stem cell transcriptional programs negative correlates with patient survival.ConclusionOur findings reveal the landscape of stemness across human solid cancers, show that tumour stemness can predict anti-cancer immunity in diverse settings, and may help to identify patients that will have improved response to immunotherapy.