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. 2023 Dec;55(12):2175-2188.
doi: 10.1038/s41588-023-01570-0. Epub 2023 Nov 20.

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

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

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

Junpeng Fan et al. Nat Genet. 2023 Dec.

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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