Impacts of neoadjuvant chemoradiotherapy on the immune landscape of esophageal squamous cell carcinomaResearch in context
Jing Wen,
Shuogui Fang,
Yi Hu,
Mian Xi,
Zelin Weng,
Chuqing Pan,
Kongjia Luo,
Yihong Ling,
Renchun Lai,
Xiuying Xie,
Xiaodan Lin,
Ting Lin,
Jiyang Chen,
Qianwen Liu,
Jianhua Fu,
Hong Yang
Affiliations
Jing Wen
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Corresponding author. State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Shuogui Fang
Department of Thoracic Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
Yi Hu
Department of Thoracic Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
Mian Xi
Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Department of Radiotherapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
Zelin Weng
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
Chuqing Pan
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
Kongjia Luo
Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Department of Thoracic Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
Yihong Ling
Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
Renchun Lai
Department of Anesthesiology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
Xiuying Xie
Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
Xiaodan Lin
Department of Thoracic Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
Ting Lin
Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
Jiyang Chen
Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
Qianwen Liu
Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Department of Thoracic Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Corresponding author. Department of Thoracic Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Jianhua Fu
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Department of Thoracic Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Corresponding author. Department of Thoracic Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Hong Yang
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Department of Thoracic Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Corresponding author. Department of Thoracic Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Summary: Background: Neoadjuvant chemoradiotherapy (neoCRT) followed by surgery is the most common approach for locally advanced resectable esophageal squamous cell carcinoma (ESCC) patients. How neoCRT impacts ESCC tumor immune microenvironment (TIME) has not been fully understood. Methods: Single-cell RNA sequencing (scRNA-seq) was conducted to examine the neoCRT-driven cellular and molecular dynamics in 8 pre- and 7 post-neoCRT ESCC samples from 8 male patients. Findings: scRNA-seq data of about 112,000 cells were obtained. Expression programs of cell cycle, epithelium development, immune response, and extracellular structure in pre-treatment tumor cells were related to neoCRT response. Spearman correlation between CD8+ T cells' cytotoxicity and expression of checkpoint molecules was prominent in pre-neoCRT intermediate activated/exhausted CD8+ T cells. NeoCRT increased CD8+ T cells’ infiltration but promoted their exhaustion in both major and minor responders. NeoCRT promoted differentiation of Th but demoted that of Treg cells in major responders. Maturation of cDC1s and expression of M2 macrophage markers increased while the number of cDC2s decreased after neoCRT. Higher activities of immune-related pathways in pre-neoCRT CD8+ T cells and macrophages, as well as a pronounced decrease of them after neoCRT, correlated with better neoCRT response. Interactions between intermediate activated/exhausted CD8+ T and macrophages, cDC1s, and LAMP3+ cDCs decreased after neoCRT. Interpretation: Our comprehensive picture of the neoCRT-related immune changes provides deeper insights into immunological mechanisms associated with ESCC response to neoCRT, which may aid in future development of immune-strategies for improving ESCC treatment. Funding: This work was supported by the National Natural Science Foundation of China (82072607).
