1 - Improved Survival Outcomes in Pancreatic Adenocarcinoma Associated With Intratumoral Bacteroides Abundance and Decreased Regulatory T-Cell Infiltrate

Daniel Segarra, MD¹, Saif Zaman, MD², George Chen, MD², Shaffer R. S.. Mok, MD^3
1University of South Florida Health, Tampa, FL; ²Yale University School of Medicine, New Haven, CT; ³Moffitt Cancer Center, Tampa, FL

Introduction: Bacteroides fragilis toxin has been associated with a procarcinogenic cascade through mediation of IL-17 expression. As such, we hypothesized that alterations in the abundance of Bacteroides in the intratumor microbiome of pancreatic adenocarcinoma (PAAD) could affect tumor infiltrating immune cell density. Here we assess the associations of intratumoral Bacteroides RNA signatures in PAAD across different survival types and with intratumoral T-regulatory cell abundance.

Methods: Intratumoral microbial RNA sequencing (RNA-seq) data were obtained from The Cancer Genome Atlas (TCGA) pancreatic adenocarcinoma (PAAD) database on cBioPortal.org and procured as described by Poore et al. (Nature, 2020). Average log2 counts per million (CPM) of Bacteroides for each patient. Intratumoral immune cell abundance was estimated via the quanTIseq method described previously by Finotello et al. (Genome Medicine, 2019). Kaplan-Meier analysis was done using the lifelines python package. Relative hazard ratios (HRs) for progression-free, disease-specific, disease-free, and overall survival were estimated using multivariate Cox proportional hazards models using the lifelines python package. Age, gender, and stage were included as covariates. Microbial abundance was correlated with immune cell abundance using Spearman correlation analysis using the python scipy package. The p-value level of significance was set at < 0.05 for independent tests.

Results: Our study included 177 patients with PAAD and Bacteroides RNA-seq data. Comparison of the rate of survival for patients in the top and bottom halves of Bacteroides log CPM showed higher abundance was associated with significantly increased overall (p = 0.0003), progression-free (p < 0.0001), disease-specific (p < 0.0001), and disease-free survival (p < 0.0001)(Figure 1). Our multivariate cox proportional hazards model demonstrated that individuals with increased Bacteroides abundance in pancreatic adenocarcinoma were associated with decreased risk of disease progression (HR 0.43; p = 0.0001). Spearman correlation analysis interestingly demonstrated that intratumoral Bacteroides abundance is significantly negatively correlated with T Regulatory Cell abundance (correlation coefficient = -0.161; p = 0.0307).

Discussion: Our results suggest that patients with increased Bacteroides genetic signatures in PAAD tumor samples have improved survival outcomes, perhaps due in part to decreased T-regulatory cell infiltrate, which would suggest improved immune reactivity.




Disclosures:


Daniel Segarra, MD¹, Saif Zaman, MD², George Chen, MD², Shaffer R. S.. Mok, MD³, 1, Improved Survival Outcomes in Pancreatic Adenocarcinoma Associated With Intratumoral Bacteroides Abundance and Decreased Regulatory T-Cell Infiltrate, ACG 2023 Annual Scientific Meeting Abstracts. Vancouver, BC, Canada: American College of Gastroenterology.