Abstract
BackgroundLimited studies examine the immune landscape in Esophageal Adenocarcinoma (EAC). We aim to identify novel associations, which may inform immunotherapy treatment stratification.MethodsThree hundred twenty-nine EAC cases were available in Tissue Microarrays (TMA) format. A discovery cohort of 166 EAC cases were stained immunohistochemically for range of adaptive immune (CD3, CD4, CD8 and CD45RO) and immune checkpoint biomarkers (ICOS, IDO-1, PD-L1, PD-1). A validation cohort of 163 EAC cases was also accessed. A digital pathology analysis approach was used to quantify biomarker density.ResultsCD3, CD4, CD8, CD45RO, ICOS and PD-1 were individually predictive of better overall survival (OS) (Log rank p = < 0.001; p = 0.014; p = 0.001; p = < 0.001; p = 0.008 and p = 0.026 respectively). Correlation and multivariate analysis identified high CD45RO/ICOS patients with significantly improved OS which was independently prognostic (HR = 0.445, (0.223–0.886), p = 0.021). Assessment of CD45RO and ICOS high cases in the validation cohort revealed an associated with improved OS (HR = 0.601 (0.363–0.996), p = 0.048). Multiplex IHC identified cellular co-expression of high CD45RO/ICOS. High CD45RO/ICOS patients have significantly improved OS.ConclusionsMultiplexing identifies true cellular co-expression. These data demonstrate that co-expression of immune biomarkers are associated with better outcome in EAC and may provide evidence for immunotherapy treatment stratification.
Highlights
Limited studies examine the immune landscape in Esophageal Adenocarcinoma (EAC)
A validation set of 163 resected gastro-oesophageal adenocarcinoma cases represented on five Tissue Microarrays (TMA) was obtained from the Grampian biorepository, diagnosed within the Grampian National Health Service Scotland from 2004 to 2010, accessed through the Grampian Biorepository (OREC 18/LO/0161), which has been previously described [20]
Validated biomarker expression Cellular expression of CD3, CD4, CD8 and CD45RO was observed as strong membrane staining as expected, with characteristic, strong and fine, membrane staining seen for the PD-L1 clone SP263
Summary
Limited studies examine the immune landscape in Esophageal Adenocarcinoma (EAC). We aim to identify novel associations, which may inform immunotherapy treatment stratification. Five year survival rates remain poor at 17% and for resectable disease this figure remains at approximately 45% despite improvements in surgery and neo-adjuvant therapy. The wide variability in patient outcome following resection is indicative of the need for robust biomarkers for prognostication, even following the improved survival rates seen with the introduction of neo-adjuvant chemotherapy [2, 3]. Response to checkpoint inhibition has been shown to be more effective in tumours with a higher mutational load [4]. These tumour types are increasingly being considered as potential targets for immunotherapy. EAC is one example of a tumour type with a high mutational frequency with as many as three hundred thousand mutations per tumour [5]
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