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EP047/#376  Multi-omics characterization of cellular state diversity and bidirectional tumor-stroma/immune interactions in cervical squamous cell carcinoma
  1. Gang Chen,
  2. Junpeng Fan and
  3. Chaoyang Sun
  1. Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, National Clinical Research Center for Gynecology and Obstetrics, Wuhan, China


Introduction Cervical cancer ranks as the fourth leading cause of cancer-related deaths among women, with low response rates to immune-checkpoint blockade (ICB).

Methods Here we conducted a multidimensional analysis encompassing single-cell RNA-seq (scRNA-seq), spatial transcriptomics, and spatial proteomics, combined with genetic and pharmacological perturbations to systematically develop a high-resolution and spatially-resolved map of intra-tumoral expression heterogeneity in cervical squamous cell carcinoma (CSCC).

Results Three context-specific tumor states (Epithelial-cytokeratin (Epi-Krt), epithelial-immune (Epi-imm) and epithelial senescence (Epi-Sen)) that recapitulate squamous differentiation substantially alter the tumor immune microenvironment (TIME). Bidirectional interactions between Epi-Krt malignant epithelial cells and MMP11+ CAF form an immune exclusionary microenvironment through TGFβ pathway signaling mediated by FABP5. Epi-Imm malignant epithelial cells and NK/T cells interact bidirectionally through interferon signaling. Notably, preliminary analysis of the NACI clinical trial (NCT04516616) demonstrated neoadjuvant chemotherapy (NACT) induce a state transition to Epi-Imm with the extent of this transition being associated with pathological complete remission (pCR) to subsequent ICB treatment.

Conclusion/Implications These findings provide a comprehensive and nuanced understanding of cellular state diversity and have significant implications for developing novel therapeutic strategies in CSCC and potentially other squamous cancers.

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