Fecal Microbiome Composition Correlates with Pathologic Complete Response in Patients with Operable Esophageal Cancer Treated with Combined Chemoradiotherapy and Immunotherapy

Fyza Y Shaikh; Seoho Lee; James R White; Yujie Zhao; Jacqueline T Ferri; Gavin Pereira; Blair V Landon; Suqi Ke; Chen Hu; Josephine L Feliciano; Russell K Hales; K Ranh Voong; Richard J Battafarano; Stephen C Yang; Stephen Broderick; Jinny Ha; Elizabeth Thompson; Eun J Shin; David L Bartlett; Benny Weksler; Drew M Pardoll; Valsamo Anagnostou; Vincent K Lam; Ali H Zaidi; Ronan J Kelly; Cynthia L Sears

doi:10.3390/cancers16213644

Fecal Microbiome Composition Correlates with Pathologic Complete Response in Patients with Operable Esophageal Cancer Treated with Combined Chemoradiotherapy and Immunotherapy

Cancers (Basel). 2024 Oct 29;16(21):3644. doi: 10.3390/cancers16213644.

Authors

Fyza Y Shaikh^{1

2

3}, Seoho Lee⁴, James R White⁵, Yujie Zhao⁶, Jacqueline T Ferri¹, Gavin Pereira², Blair V Landon², Suqi Ke^{2

7}, Chen Hu^{2

7}, Josephine L Feliciano^{1

2}, Russell K Hales^{2

8}, K Ranh Voong^{2

8}, Richard J Battafarano⁹, Stephen C Yang⁹, Stephen Broderick⁹, Jinny Ha⁹, Elizabeth Thompson¹⁰, Eun J Shin⁴, David L Bartlett¹¹, Benny Weksler¹¹, Drew M Pardoll^{1

2

3}, Valsamo Anagnostou^{1

2

3}, Vincent K Lam^{1

2}, Ali H Zaidi¹¹, Ronan J Kelly¹², Cynthia L Sears^{1

2

3

4}

Affiliations

¹ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ The Bloomberg-Kimmel Institute of Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁵ Resphera Biosciences, Baltimore, MD 21231, USA.
⁶ Department of Biomedical Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD 21218, USA.
⁷ Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
⁸ Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁹ Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
¹⁰ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
¹¹ Allegheny Health Network Cancer Institute, Allegheny Health Network, Pittsburgh, PA 15212, USA.
¹² The Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX 75246, USA.

Abstract

Background: Preclinical and clinical data indicate that chemoradiotherapy (CRT) in combination with checkpoint inhibitors may prime an anti-tumor immunological response in esophageal cancer. However, responses to neoadjuvant therapy can vary widely and the key biomarkers to determine response remain poorly understood. The fecal microbiome is a novel and potentially modifiable biomarker of immunotherapy response, and both fecal and tumor microbes have been found to associate with outcomes in esophageal cancer. Methods: Fecal and tumor samples were collected from patients with stage II-III resectable esophageal or gastroesophageal junction carcinoma treated with neoadjuvant immune checkpoint inhibitors (ICIs) plus CRT prior to surgical resection. Microbiome profiles were analyzed by 16S rRNA amplicon sequencing and taxonomic data were integrated with fecal metabolite analysis to assess microbial function. Results: The fecal microbiome of patients with pathological complete response (PCR) grouped in distinct clusters compared to patients with residual viable tumor (RVT) by Bray-Curtis diversity metric. Integrated taxonomic and metabolomic analysis of fecal samples identified a sphingolipid and primary bile acid as enriched in the PCR, the levels of which correlated with several bacterial species: Roseburis inulinivorans, Ruminococcus callidus, and Fusicantenibacter saccharivorans. Analysis of the tumor microbiome profiles identified several bacterial genera previously associated with esophageal tumors, including Streptococcus and Veillonella. Conclusions: These results further characterize the fecal and tumor microbiome of patients with operable esophageal cancer and identify specific microbes and metabolites that may help elucidate how microbes contribute to tumor response with neoadjuvant CRT combined with ICI.

Keywords: esophageal cancer; fecal microbiome; immune checkpoint inhibitors; neoadjuvant chemoradiotherapy.

Grants and funding

The clinical study was funded by Bristol Myers Squibb. The funder had no role in study design, data collection and analysis and decision to publish. The translational work was supported in part by the Bloomberg~Kimmel Institute for Cancer Immunotherapy (D.M.P., C.L.S., F.Y.S., V.A.), a research grant from Bristol Myers Squibb (D.M.P., C.L.S., V.A., K.N.S.), the US National Institutes of Health (grants CA121113 to V.A., R37 CA251447 to K.N.S.), a Cancer Research Institute Torrey Coast Foundation GEMINI CLIP award (to V.A. and V.L.), the ECOG-ACRIN Thoracic Malignancies Integrated Translational Science Center (grant UG1CA233259 to V.A.), the Conquer Cancer Foundation of ASCO Career Development Award (to V.L.), Swim Across America (to R.K.), the W.W. Caruth Jr. Foundation (to R.K). FYS was supported in part by the US National Institutes of Health (K08CA263316) and a Damon Runyon Clinical Investigator Award.