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

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

  • Nat Genet. 2023 Nov 20. doi: 10.1038/s41588-023-01570-0.
Junpeng Fan # 1 2,  Funian Lu # 1 2,  Tianyu Qin # 1 2,  Wenju Peng # 1 2,  Xucui Zhuang 1 2,  Yinuo Li 1 2,  Xin Hou 1 2,  Zixuan Fang 1 2,  Yunyi Yang 1 2,  Ensong Guo 1 2,  Bin Yang 1 2,  Xi Li 1 2,  Yu Fu 1 2,  Xiaoyan Kang 1 2,  Zimeng Wu 1 2,  Lili Han 3,  Gordon B Mills 4 5,  Xiangyi Ma 6 7,  Kezhen Li 8 9,  Peng Wu 10 11,  Ding Ma 12 13,  Gang Chen 14 15,  Chaoyang Sun 16 17
Affiliations

Affiliations

  • 1 Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3 Department of Gynecology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China.
  • 4 Division of Oncological Sciences, Oregon Health and Sciences University, Portland, OR, USA.
  • 5 Knight Cancer Institute, Portland, OR, USA.
  • 6 Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. xyma@tjh.tjmu.edu.cn.
  • 7 National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. xyma@tjh.tjmu.edu.cn.
  • 8 Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. tjkeke@126.com.
  • 9 National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. tjkeke@126.com.
  • 10 National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. pengwu8626@tjh.tjmu.edu.cn.
  • 11 Department of Gynecological Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. pengwu8626@tjh.tjmu.edu.cn.
  • 12 Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. dma@tjh.tjmu.edu.cn.
  • 13 National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. dma@tjh.tjmu.edu.cn.
  • 14 Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. tjchengang@hust.edu.cn.
  • 15 National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. tjchengang@hust.edu.cn.
  • 16 Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. suncydoctor@gmail.com.
  • 17 National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. suncydoctor@gmail.com.
  • # Contributed equally.
PMID: 37985817 DOI: 10.1038/s41588-023-01570-0
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.

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