Multiomic analysis of cervical squamous cell carcinoma identifies cellular ecosystems with biological and clinical relevance

Junpeng Fan; Funian Lu; Tianyu Qin; Wenju Peng; Xucui Zhuang; Yinuo Li; Xin Hou; Zixuan Fang; Yunyi Yang; Ensong Guo; Bin Yang; Xi Li; Yu Fu; Xiaoyan Kang; Zimeng Wu; Lili Han; Gordon B. Mills; Xiangyi Ma; Kezhen Li; Peng Wu; Ding Ma; Gang Chen; Chaoyang Sun

doi:10.1038/s41588-023-01570-0

Multiomic analysis of cervical squamous cell carcinoma identifies cellular ecosystems with biological and clinical relevance

Junpeng Fan, Funian Lu, Tianyu Qin, Wenju Peng, Xucui Zhuang, Yinuo Li, Xin Hou, Zixuan Fang, Yunyi Yang, Ensong Guo, Bin Yang, Xi Li, Yu Fu, Xiaoyan Kang, Zimeng Wu, Lili Han, Gordon B. Mills, Xiangyi Ma, Kezhen Li, Peng WuDing Ma, Gang Chen, Chaoyang Sun

Research output: Contribution to journal › Article › peer-review

Abstract

Cervical squamous cell carcinoma (CSCC) exhibits a limited response to immune-checkpoint blockade. Here we conducted a multiomic analysis encompassing single-cell RNA sequencing, spatial transcriptomics and spatial proteomics, combined with genetic and pharmacological perturbations to systematically develop a high-resolution and spatially resolved map of intratumoral expression heterogeneity in CSCC. Three tumor states (epithelial-cytokeratin, epithelial-immune (Epi-Imm) and epithelial senescence), recapitulating different stages of squamous differentiation, showed distinct tumor immune microenvironments. Bidirectional interactions between epithelial-cytokeratin malignant cells and immunosuppressive cancer-associated fibroblasts form an immune exclusionary microenvironment through transforming growth factor β pathway signaling mediated by FABP5. In Epi-Imm tumors, malignant cells interact with natural killer and T cells through interferon signaling. Preliminary analysis of samples from a cervical cancer clinical trial (NCT04516616) demonstrated neoadjuvant chemotherapy induces a state transition to Epi-Imm, which correlates with pathological complete remission following treatment with immune-checkpoint blockade. These findings deepen the understanding of cellular state diversity in CSCC.

Original language	English (US)
Pages (from-to)	2175-2188
Number of pages	14
Journal	Nature genetics
Volume	55
Issue number	12
DOIs	https://doi.org/10.1038/s41588-023-01570-0
State	Published - Dec 2023

ASJC Scopus subject areas

Genetics

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Fan, J., Lu, F., Qin, T., Peng, W., Zhuang, X., Li, Y., Hou, X., Fang, Z., Yang, Y., Guo, E., Yang, B., Li, X., Fu, Y., Kang, X., Wu, Z., Han, L., Mills, G. B., Ma, X., Li, K., ... Sun, C. (2023). Multiomic analysis of cervical squamous cell carcinoma identifies cellular ecosystems with biological and clinical relevance. Nature genetics, 55(12), 2175-2188. https://doi.org/10.1038/s41588-023-01570-0

Fan, J, Lu, F, Qin, T, Peng, W, Zhuang, X, Li, Y, Hou, X, Fang, Z, Yang, Y, Guo, E, Yang, B, Li, X, Fu, Y, Kang, X, Wu, Z, Han, L, Mills, GB, Ma, X, Li, K, Wu, P, Ma, D, Chen, G & Sun, C 2023, 'Multiomic analysis of cervical squamous cell carcinoma identifies cellular ecosystems with biological and clinical relevance', Nature genetics, vol. 55, no. 12, pp. 2175-2188. https://doi.org/10.1038/s41588-023-01570-0

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title = "Multiomic analysis of cervical squamous cell carcinoma identifies cellular ecosystems with biological and clinical relevance",

abstract = "Cervical squamous cell carcinoma (CSCC) exhibits a limited response to immune-checkpoint blockade. Here we conducted a multiomic analysis encompassing single-cell RNA sequencing, spatial transcriptomics and spatial proteomics, combined with genetic and pharmacological perturbations to systematically develop a high-resolution and spatially resolved map of intratumoral expression heterogeneity in CSCC. Three tumor states (epithelial-cytokeratin, epithelial-immune (Epi-Imm) and epithelial senescence), recapitulating different stages of squamous differentiation, showed distinct tumor immune microenvironments. Bidirectional interactions between epithelial-cytokeratin malignant cells and immunosuppressive cancer-associated fibroblasts form an immune exclusionary microenvironment through transforming growth factor β pathway signaling mediated by FABP5. In Epi-Imm tumors, malignant cells interact with natural killer and T cells through interferon signaling. Preliminary analysis of samples from a cervical cancer clinical trial (NCT04516616) demonstrated neoadjuvant chemotherapy induces a state transition to Epi-Imm, which correlates with pathological complete remission following treatment with immune-checkpoint blockade. These findings deepen the understanding of cellular state diversity in CSCC.",

author = "Junpeng Fan and Funian Lu and Tianyu Qin and Wenju Peng and Xucui Zhuang and Yinuo Li and Xin Hou and Zixuan Fang and Yunyi Yang and Ensong Guo and Bin Yang and Xi Li and Yu Fu and Xiaoyan Kang and Zimeng Wu and Lili Han and Mills, {Gordon B.} and Xiangyi Ma and Kezhen Li and Peng Wu and Ding Ma and Gang Chen and Chaoyang Sun",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.",

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doi = "10.1038/s41588-023-01570-0",

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AU - Fan, Junpeng

AU - Lu, Funian

AU - Qin, Tianyu

AU - Peng, Wenju

AU - Zhuang, Xucui

AU - Li, Yinuo

AU - Hou, Xin

AU - Fang, Zixuan

AU - Yang, Yunyi

AU - Guo, Ensong

AU - Yang, Bin

AU - Li, Xi

AU - Fu, Yu

AU - Kang, Xiaoyan

AU - Wu, Zimeng

AU - Han, Lili

AU - Mills, Gordon B.

AU - Ma, Xiangyi

AU - Li, Kezhen

AU - Wu, Peng

AU - Ma, Ding

AU - Chen, Gang

AU - Sun, Chaoyang

PY - 2023/12

Y1 - 2023/12

N2 - Cervical squamous cell carcinoma (CSCC) exhibits a limited response to immune-checkpoint blockade. Here we conducted a multiomic analysis encompassing single-cell RNA sequencing, spatial transcriptomics and spatial proteomics, combined with genetic and pharmacological perturbations to systematically develop a high-resolution and spatially resolved map of intratumoral expression heterogeneity in CSCC. Three tumor states (epithelial-cytokeratin, epithelial-immune (Epi-Imm) and epithelial senescence), recapitulating different stages of squamous differentiation, showed distinct tumor immune microenvironments. Bidirectional interactions between epithelial-cytokeratin malignant cells and immunosuppressive cancer-associated fibroblasts form an immune exclusionary microenvironment through transforming growth factor β pathway signaling mediated by FABP5. In Epi-Imm tumors, malignant cells interact with natural killer and T cells through interferon signaling. Preliminary analysis of samples from a cervical cancer clinical trial (NCT04516616) demonstrated neoadjuvant chemotherapy induces a state transition to Epi-Imm, which correlates with pathological complete remission following treatment with immune-checkpoint blockade. These findings deepen the understanding of cellular state diversity in CSCC.

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Multiomic analysis of cervical squamous cell carcinoma identifies cellular ecosystems with biological and clinical relevance

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