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Modeling Oral-Esophageal Squamous Cell Carcinoma in 3D Organoids
Published on: December 23, 2022
DNA damage repair profiling of esophageal squamous cell carcinoma uncovers clinically relevant molecular subtypes
Ning Zhao1, Zicheng Zhang2, Qiang Wang3
1State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, PR China.
Background:
DNA damage repair (DDR) is a critical process that maintains genomic integrity and plays essential roles at both the cellular and organismic levels. Here, we aimed to characterize the DDR profiling of esophageal squamous cell carcinoma (ESCC), investigate the prognostic value of DDR-related features, and explore their potential for guiding personalized treatment strategies.
Methods:
We analyzed bulk and single-cell transcriptomics data from 377 ESCC cases from our institution and other publicly available cohorts to identify major DDR subtypes. The heterogeneity in cellular and functional properties, tumor microenvironment (TME) characteristics, and prognostic significance of these DDR subtypes were investigated using immunogenomic analysis and in vitro experiments. Additionally, we experimentally validated a combinatorial immunotherapy strategy using syngeneic mouse models of ESCC.
Findings:
DDR alteration profiling enabled us to identify two distinct DDR subtypes, DDRactive and DDRsilent, which exhibited independent prognostic values in locoregional ESCC but not in metastatic ESCC. The DDRsilent subtype was characterized by an inflamed but immune-suppressed microenvironment with relatively high immune cell infiltration, abnormal immune checkpoint expression, T-cell exhaustion, and enrichment of cancer-related pathways. Moreover, DDR subtyping indicates that BRCA1 and HFM1 are robust and independent prognostic factors in locoregional ESCC. Finally, we proposed and verified that the concomitant triggering of GITR or blockade of BTLA with PD-1 blockade or cisplatin chemotherapy represents effective combination strategies for high-risk locoregional ESCC tumors.
Interpretation:
Our discovery of DDR-based molecular subtypes will enhance our understanding of tumor heterogeneity and have significant clinical implications for the therapeutic and management strategies of locoregional ESCC.
Funding:
This study was supported by the National Key R&D Program of China (2021YFC2501000, 2022YFC3401003), National Natural Science Foundation of China (82172882), the Beijing Natural Science Foundation (7212085), the CAMS Innovation Fund for Medical Sciences (2021-I2M-1-018, 2021-I2M-1-067), the Fundamental Research Funds for the Central Universities (3332021091), and the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2019PT310027).
Insights
This study identifies two DNA damage repair (DDR) subtypes in esophageal squamous cell carcinoma (ESCC), revealing distinct prognostic values and potential therapeutic strategies for locoregional disease.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- DNA damage repair (DDR) is crucial for maintaining genomic integrity.
- Esophageal squamous cell carcinoma (ESCC) is a significant global health concern.
- Understanding DDR in ESCC is vital for improving patient outcomes.
Purpose of the Study:
- To characterize DDR profiling in ESCC.
- To investigate the prognostic value of DDR features.
- To explore DDR-based personalized treatment strategies for ESCC.
Main Methods:
- Analysis of bulk and single-cell transcriptomics data from 377 ESCC cases.
- Immunogenomic analysis and in vitro experiments to assess DDR subtypes.
- Experimental validation of combinatorial immunotherapy in syngeneic mouse models.
Main Results:
- Identification of two distinct DDR subtypes: DDRactive and DDRsilent, with prognostic value in locoregional ESCC.
- DDRsilent subtype characterized by an inflamed, immune-suppressed TME with high immune cell infiltration and T-cell exhaustion.
- BRCA1 and HFM1 identified as independent prognostic factors; validated combination therapies (GITR/BTLA with PD-1 blockade or cisplatin) for high-risk ESCC.
Conclusions:
- Discovery of DDR-based molecular subtypes enhances understanding of ESCC heterogeneity.
- These findings have significant clinical implications for therapeutic and management strategies in locoregional ESCC.
- DDR subtyping offers a promising approach for personalized treatment of ESCC.
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