Abstract 2826: Understanding associations among local microbiome, immune response, and efficacy of immunotherapy in esophageal cancer

Abstract

Although Barrett’s esophagus is the primary precursor of esophageal adenocarcinoma, the annual incidence of adenocarcinoma is 0.12% in a Barrett’s esophagus population. We hypothesized that the esophageal microbiome may be associated with mucosal immunity changes that may determine subsequent carcinogenesis. To better understand the association among the local microbiota composition, immune response and progression of esophageal cancer, we performed whole genome sequencing (WGS) and bulk RNASeq in parallel, from endoscopic biopsies (n=23) collected from patients with normal squamous cell (n=9), non-dysplastic Barrett’s esophagus (n=8) and esophageal adenocarcinoma (n = 6). Using a novel customized computational pipeline to identify and characterize bacteria from low microbial content endoscopic samples (Zhang et al, Genome Biology, 2015). WGS analysis revealed a higher microbial diversity in normal squamous cell carcinomas compared to the non-dysplastic Barrett’s esophagus with high abundance of Veilonella Parvula, Prevotella melaninogenica and Streptococcus parasanguinis. Unsupervised clustering analysis of the entire data set revealed high abundance of Fusobacterium nucleatum in adenocarcinoma samples, which has been associated with a shorter survival in esophageal cancer. To characterize the immune infiltration in the mucosal biopsy samples, we defined a 784-gene immune panel. Unsupervised clustering analysis of gene expression revealed a much higher immune infiltration in most adenocarcinoma and some non-dysplastic Barrett’s compared with normal esophageal squamous tissue samples. Especially CD4+ Th1 and Th2 helper cell as well as CD8+ T cell associated immune response are highly enriched in some adenocarcinoma and non-dysplastic Barrett’s esophageal samples. To further investigate the effect of immune tumor microenvironment on efficacy of immunotherapy, we performed single cell sequencing on matching normal and tumor tissues collected at baseline and post-treatment from 6 patients subjected to anti-PD1 therapy. Using this approach, we can identify both innate and adaptive immune cells in both pre and post treatment biopsies. We specifically observe upregulation of MHCII associated cells in post-treatment biopsies. Together, our data suggest that esophageal cancers display distinct microbial patterns associated with chronic inflammation and a tumor-promoting pro-inflammatory microenvironment. Note: This abstract was not presented at the meeting. Citation Format: Chao Zhang, Prashant V. Thakkar, Prateek Sharma, Sreekar Vennelaganti, Doron Betel, Manish A. Shah. Understanding associations among local microbiome, immune response, and efficacy of immunotherapy in esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2826.