Multiomic analysis of cervical squamous cell carcinoma identifies cellular ecosystems with biological and clinical relevance.
Junpeng FanFunian LuTianyu QinWenju PengXucui ZhuangYinuo LiXin HouZixuan FangYunyi YangEnsong GuoBin YangXi LiYu FuXiaoyan KangZimeng WuLili HanGordon B MillsXiangyi MaKezhen LiPeng WuDing MaGang ChenChaoyang SunPublished in: Nature genetics (2023)
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.
Keyphrases
- single cell
- squamous cell carcinoma
- neoadjuvant chemotherapy
- transforming growth factor
- induced apoptosis
- rna seq
- locally advanced
- clinical trial
- high resolution
- cell cycle arrest
- epithelial mesenchymal transition
- high throughput
- genome wide
- stem cells
- endoplasmic reticulum stress
- poor prognosis
- lymph node
- binding protein
- randomized controlled trial
- lymph node metastasis
- climate change
- endothelial cells
- dna damage
- radiation therapy
- rectal cancer
- rheumatoid arthritis
- open label
- dna methylation
- extracellular matrix
- copy number
- phase iii
- ulcerative colitis