17 Quantifying microenvironmental signatures of oesophageal carcinogenesis

Abstract

IntroductionThe tumour-immune crosstalk has been successfully exploited in recent immunotherapy trials, with clear impact in several highly mutated late stage cancers. To what extent it may be exploited at an earlier stage in the cancer’s history is currently unclear. Oesophageal adenocarcinoma is a cancer with dismal survival and early onset of metastases. We have previously described three subtypes of this cancer with distinct therapeutic relevance based on signatures of mutational processes observed during cancer development. Secrier, Li et al, Nat Genet 2016 In particular, an acid reflux-linked signature defines a subgroup of patients with enhanced immune activity that may benefit from immunotherapy approaches. In this work we question whether similar features of tumour-immune crosstalk may precipitate cancer progression in the oesophagus.Material and methodsAiming to explore multiple aetiology backgrounds, we employed a cohort of oesophageal tumours from the Cancer Genome Atlas (n=184) incorporating both adenocarcinomas and squamous cell carcinomas. We used extensively curated signatures of immune function and in-house computational methods to score immune activity from bulk RNA-seq data. Matched whole-exome sequencing data was used to quantify signatures of selected mutational processes and features of genomic instability.Results and discussionsThe activity of cancer associated fibroblasts was significantly associated with defined markers of cancer progression, both in adenocarcinomas as well as squamous cell carcinomas. Signals of rapid cancer progression were stronger in the highly immunogenic subtype, and were accompanied by elevated patterns of macrophage activity, defined on a spectrum of inhibition to stimulation signals. These immune determinants of progression showed similar trends across tissues. Subsequent integration of genomic instability characteristics and specific mutational triggers suggested that complex tumour-immune interactions may be contributing to oesophageal cancer progression in a subtype-specific manner.ConclusionWe have previously demonstrated that historic mutational processes in oesophageal adenocarcinoma unveil distinct trajectories of cancer development, with differentiated impact on immune composition. This work shows a strong microenvironmental contribution to rapid cancer progression, and highlights the importance of stromal cell dynamics in this process. We propose quantifiable features of tumour-immune crosstalk in oesophageal cancer subtypes with potential predictive value.