Abstract
The outcome in esophageal adenocarcinoma (EAC) is still poor with only 20% of patients in Western populations surviving for more than 5 years. Almost nothing is known about the precise composition of immune cells and their gene expression profiles in primary resected EACs and also nothing compared to neoadjuvant treated EACs. This study analyzes and compares immune profiles of primary resected and neoadjuvant treated esophageal adenocarcinoma and unravels possible targets for immunotherapy. We analyzed 47 EAC in total considering a set of 30 primary treatment-naive EACs and 17 neoadjuvant pretreated (12 × CROSS, 5 × FLOT) using the Nanostring's panel-based gene expression platform including 770 genes being important in malignant tumors and their immune micromileu. Most of the significantly altered genes are involved in the regulation of immune responses, T-and B cell functions as well as antigen processing. Chemokine-receptor axes like the CXCL9, -10,-11/CXCR3- are prominent in esophageal adenocarcinoma with a fold change of up to 9.5 promoting cancer cell proliferation and metastasis. ARG1, as a regulator of T-cell fate is sixfold down-regulated in untreated primary esophageal tumors. The influence of the currently used neoadjuvant treatment revealed a down-regulation of nearly all important checkpoint markers and inflammatory related genes in the local microenvironment. We found a higher expression of checkpoint markers like LAG3, TIM3, CTLA4 and CD276 in comparison to PD-L1/PD-1 supporting clinical trials analyzing the efficacy of a combination of different checkpoint inhibitors in EACs. We found an up-regulation of CD38 or LILRB1 as examples of additional immune escape mechanism.
Highlights
Esophageal adenocarcinoma (EAC) is associated with the sixth-highest cancer-related mortality and increasing incidences mainly in the Western World [1, 2]
We asked whether inhibition of macrophage phagocytosis by MHC class I could be altered in esophageal tumor specimen by an alternative way to interfere with antigen processing
Checkpoint-inhibitors like pembrolizumab and nivolumab which have proven to be effective, inter alia, in the treatment of malignant melanoma and NSCLCs are tested in different Phase III for esophageal cancer
Summary
Esophageal adenocarcinoma (EAC) is associated with the sixth-highest cancer-related mortality and increasing incidences mainly in the Western World [1, 2]. Curative treatment consists mostly of a multimodal therapy of esophageal en-bloc resection and perioperative radio-chemotherapy, but compared to other cancer entities the outcome is still poor with only 20% of patients in Western populations surviving for more than 5 years [3,4,5]. The interaction of tumor cells and associated immune compartment is supposed to play an important role in cancer progression. First line and second line treatment of metastatic esophageal cancer with checkpoint inhibitors considering the PD1/PDL1 axis are currently tested in a Phase III evaluation with pembrolizumab (KEYNOTE-062, KEYNOTE-061) [14] as well as nivolumab (CheckMate-577) in the adjuvant setting with various other approaches in all lines of therapy [15]
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