Single-cell and spatial transcriptomics delineate the remodeling of esophageal squamous-cell carcinoma ecosystem following diverse therapies.

Abstract

It remains elusive how various therapeutic approaches, including radiotherapy, chemoradiotherapy, and immunoradiotherapy, reshape malignant cells and the tumor microenvironments (TMEs) during esophageal squamous cell carcinoma (ESCC) progression. A mouse model of ESCC induced by 4-nitroquinoline-1-oxide was constructed and handled by therapeutic regimens including radiotherapy, chemoradiotherapy and immunoradiotherapy, followed by single-cell and spatial transcriptomics sequencing. Besides, ESCC tumors were collected from patients during surgery after chemoradiotherapy or immunoradiotherapy. Immunohistochemical staining or immunofluorescence was applied to detect markers associated with a certain treatment. By combining single-cell and spatial transcriptomics, we have deciphered the aberrant gene expression program in epithelial cells and the cellular compositions in the ESCC mouse model following different therapeutic interventions, where chemoradiotherapy moderated epithelial cells essentially by circumscribing several oncogenes and limiting their crosstalk with Hgegf + macrophages. When radiotherapy, chemoradiotherapy, and immunoradiotherapy all lessened the immunosuppressive TMEs, including regulatory T cells and Col12a1 + cancer-associated fibroblasts, immunoradiotherapy might regulate immune responses, especially as evidenced by the frequencies of Ccl5 + Cd8 + T cells elevated. Here, we mapped a comprehensive single-cell and spatial transcriptional panorama of therapy-related ESCC in mouse models. Discovering these spatiotemporal clues might have clinical implications in establishing and improving effective therapy based on these molecules for ESCC.