2666 - Gut Microbiota Predicts Risk of Treatment-related Pneumonitis in Esophageal Cancer Patients Treated with Immune-based Combination Therapy
Presenter(s)
Y. Yi1, L. Xu1, Z. Liu2, and X. Fu1; 1Department of Radiation Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, 2Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai, Shanghai, China
Purpose/Objective(s): While immunotherapy provides significant therapeutic benefits in the multidisciplinary management of esophageal cancer, it concurrently increases risk of treatment-related pneumonitis (TRP). The underlying mechanisms and predictive biomarkers for TRP remain poorly defined. Given the established immunoregulatory role of microbiota, this study sought to evaluate the feasibility of gut microbiota for TRP prediction and to investigate the potential immuno-metabolic pathways involved.
Materials/Methods: We prospectively profiled stool microbiota (16S rRNA sequencing) and serum cytokines in 50 patients with esophageal cancer undergoing chemo-immunotherapy followed by radiotherapy or esophagectomy. TRP was independently graded by two physicians according to the Common Terminology Criteria for Adverse Events version 5.0. Differential functional pathways related to microbial metabolites were validated via short-chain fatty acid (SCFA)-targeted metabolomic analysis. A random forest classifier was developed to evaluate the efficacy of identified biomarkers for TRP risk prediction.
Results: The incidence of any-grade TRP was 40% (20/50) over a median follow-up of 11.3 months. Serum IL-17 level was significantly elevated in patients who developed TRP (TRP+) compared to those who did not (TRP-) (4.24 pg/ml vs 1.14 pg/ml; p = 0.002), independent of clinicopathological characteristics, like tobacco exposure, pre-existing lung disease and lung dosimetry, etc. Microbiota analysis revealed an enrichment of Lactobacillus and several SCFA-producers (e.g., Veillonella, Romboutsia) capable of fermenting lactate into SCFA in TRP- group. Abundance of Lactobacillus was negatively correlated with IL-17 level (rho = -0.67, adjusted q < 0.01), we speculate that this association reflects the capacity of Lactobacillus to foster SCFA production thereby suppressing pro-inflammatory cytokine secretion, as supported by significantly higher levels of acetate, propionate and butyrate in TRP- group (p < 0.05 for all). Conversely, sphingolipid-producing Prevotella was overrepresented in TRP+ group and positively correlated with IL-17 secretion (rho = 0.65, adjusted q < 0.01). Functional analysis corroborated these findings, demonstrating upregulated sphingolipid signaling and metabolism pathways in TRP+ group. The receiver operating characteristic analysis yielded the largest area under the curve of 0.87 (95% confidence interval: 0.77-0.97) with predictors including Lactobacillus and Veillonella, therefore supporting them as robust predictive biomarkers for TRP.
Conclusion: The gut microbiota and derived metabolites modulate host susceptibility to TRP via regulating IL-17, which holds translational value for predicting pneumonitis risk in esophageal cancer patients receiving multidisciplinary therapy. Further validation in larger cohorts is warranted in the context of increasing immunotherapy utilization.