Abstract
Esophageal adenocarcinoma (EAC) develops from Barrett’s esophagus (BE), a chronic inflammatory state that can progress through a series of transformative dysplastic states before tumor development. While molecular and genetic changes of EAC tumors have been studied, immune microenvironment changes during Barrett’s progression to EAC remain poorly understood. In this study, we identify potential immunologic changes that can occur during BE-to-EAC progression. RNA sequencing (RNA-Seq) analysis on tissue samples from EAC patients undergoing surgical resection demonstrated that a subset of chemokines and cytokines, most notably IL6 and CXCL8, increased during BE progression to EAC. xCell deconvolution analysis investigating immune cell population changes demonstrated that the largest changes in expression during BE progression occurred in M2 macrophages, pro–B cells, and eosinophils. Multiplex immunohistochemical staining of tissue microarrays showed increased immune cell populations during Barrett’s progression to high-grade dysplasia. In contrast, EAC tumor sections were relatively immune poor, with a rise in PD-L1 expression and loss of CD8+ T cells. These data demonstrate that the EAC microenvironment is characterized by poor cytotoxic effector cell infiltration and increased immune inhibitory signaling. These findings suggest an immunosuppressive microenvironment, highlighting the need for further studies to explore immune modulatory therapy in EAC.
Highlights
The events by which Barrett’s esophagus (BE) develops into esophageal adenocarcinoma (EAC) are secondary to a series of transformative steps whereby BE is established in response to nonerosive reflux, followed by progression to low-grade dysplasia (LGD), high-grade dysplasia (HGD), and EAC
RNA sequencing (RNA-Seq) was performed on a panel of 65 patient samples representing nondysplastic BE (NDBE) + BE/LGD (n = 25), HGD < 35% (n = 8), HGD > 35% (n = 21), and EAC (n = 11)
There are subtle differences as BE progresses from LGD to HGD and EAC, demonstrating that, in a subset of patients, immune changes associated with cancer formation occur in a stepwise fashion as opposed to abrupt changes in cellular composition
Summary
The events by which Barrett’s esophagus (BE) develops into esophageal adenocarcinoma (EAC) are secondary to a series of transformative steps whereby BE is established in response to nonerosive reflux, followed by progression to low-grade dysplasia (LGD), high-grade dysplasia (HGD), and EAC. The histopathologic progression is accompanied by genomic and molecular changes, including loss of the tumor suppressive function of TP53 [1, 2]. Previous works have demonstrated the role of cytokines IL-6, CXCL8 (IL-8), TGF-β, and IL-17A in BE-to-EAC progression [4,5,6,7,8]. Work on the roles of specific immune cell subsets, such as Tregs, tumor-associated macrophages (TAM), and myeloid-derived suppressor cells (MDSC) demonstrate their ability to exert effects on tumor biology, including initiating metastasis and impacting the prognostic importance of these cell types in EAC patients [9,10,11,12]. Efficacy of immune checkpoint inhibition in metastatic EAC has been mixed with response rates usually less than 20%, suggesting that there is more to be learned about the EAC immune microenvironment [16,17,18,19,20,21]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
