Intratumoral microbiome impacts immune infiltrates in tumor microenvironment and predicts prognosis in esophageal squamous cell carcinoma patients

Shuyue Zhang; Shuishen Zhang; Xiaofan Ma; Jing Zhan; Chuqing Pan; Huizhong Zhang; Xiuying Xie; Jing Wen; Xuan Xie

doi:10.3389/fcimb.2023.1165790

Intratumoral microbiome impacts immune infiltrates in tumor microenvironment and predicts prognosis in esophageal squamous cell carcinoma patients

Front Cell Infect Microbiol. 2023 Apr 27:13:1165790. doi: 10.3389/fcimb.2023.1165790. eCollection 2023.

Authors

Shuyue Zhang^{1

2}, Shuishen Zhang³, Xiaofan Ma^{1

2}, Jing Zhan⁴, Chuqing Pan⁵, Huizhong Zhang^{1

2}, Xiuying Xie^{6

7}, Jing Wen^{6

7}, Xuan Xie^{1

2}

Affiliations

¹ Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
² Department of Thoracic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
³ Department of Thoracic Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
⁴ Department of Cardiothoracic Surgery, the First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, China.
⁵ Department of Intern Medicine, Zhuhai People's Hospital, Zhuhai, China.
⁶ State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
⁷ Guangdong Esophageal Cancer Institute, Guangzhou, China.

Abstract

Background: Different intratumoral microbiotaexist in different tumors and play a crucial function in carcinogenesis. However, whether they impact clinical outcomes in esophageal squamous cell carcinoma (ESCC) and their mechanism remain unclear.

Methods: 16S rDNA amplicon sequencing was performed on surgically resected samples from 98 ESCC patients to analyze intratumoral microbiome abundance and composition. Multiplex fluorescent immunohistochemistry staining was used to profile the phenotypes of immune infiltrates in the tumor microenvironment (TME).

Results: Patients with higher intratumoral Shannon index had significantly worse surgical outcomes. When patients were divided into short-term survivors and long-term survivors based on the median survival time, both intratumoral alpha-diversity and beta-diversity were found to be significantly inconsistent, and the relative abundance of Lactobacillus and Leptotrichia emerged as the two microorganisms that probably influenced the survival of ESCC patients. Only Lactobacillus in ESCC was validated to significantly worsen patients' prognoses and to be positively correlated with the Shannon index. Multivariate analysis revealed that the intratumoral Shannon index, the relative abundance of Lactobacillus, and the pathologic tumor-node-metastasis (pTNM) stage were independently associated with patients' overall survival. Furthermore, the relative abundance of both Lactobacillus and Shannon index was positively correlated with the proportions of PD-L1⁺ epithelial cells (ECs) and tumor-associated macrophages (TAMs). The Shannon index was negatively correlated with the proportions of natural killer (NK) cells in the TME.

Conclusions: A high abundance of intratumoral Lactobacillus and bacterial alpha-diversity was associated with the formation of the immunosuppressive TME and predicted poor long-term survival in ESCC patients.

Keywords: Lactobacillus; esophageal squamous cell carcinoma; intratumoral microbiome; prognosis; tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Squamous Cell*
Esophageal Neoplasms* / pathology
Esophageal Squamous Cell Carcinoma* / pathology
Humans
Killer Cells, Natural
Tumor Microenvironment

Grants and funding

This work was supported by grants from the National Natural Science Foundation of China under Grant [number 82072607], National Natural Science Foundation of China under Grant [number 81871975], Open Funds of State Key Laboratory of Oncology in South China under Grant [number HN2021-03], and Guangdong Science and Technology Department (2020B1212060018).