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Key Genetic Determinants Driving Esophageal Squamous Cell Carcinoma Initiation and Immune Evasion

Kyung-Pil Ko1, Yuanjian Huang2, Shengzhe Zhang1

  • 1Department of Experimental Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Gastroenterology
|May 31, 2023
PubMed
Abstract

Insights

Loss of TP53, CDKN2A, and NOTCH1 genes initiates esophageal squamous cell carcinoma (ESCC) by promoting cell changes and immune evasion. Targeting CCL2 may offer a new therapeutic strategy for this cancer subtype.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Esophageal squamous cell carcinoma (ESCC) pathogenesis remains unclear despite advances in genetic and epigenetic research.
  • Understanding ESCC initiation mechanisms is crucial for developing effective treatments.

Purpose of the Study:

  • To investigate the genetic drivers of ESCC initiation using a murine organoid model.
  • To identify molecular mechanisms underlying ESCC development and immune evasion.

Main Methods:

  • CRISPR/Cas9 gene editing was employed to target nine key genes in murine esophageal organoids.
  • Single-cell RNA sequencing was used to analyze transcriptomic changes and chemokine profiles.
  • Allograft transplantation models assessed tumorigenicity and immune evasion.
  • Human ESCC datasets were analyzed for patient stratification and correlation with organoid models.

Main Results:

  • The triple knockout of TP53, CDKN2A, and NOTCH1 (PCN) induced neoplastic features, cell lineage heterogeneity, and plasticity in esophageal organoids.
  • PCN knockout created an immunosuppressive tumor microenvironment by recruiting exhausted T cells and M2 macrophages via the CCL2-CCR2 pathway.
  • CDKN2A inactivation was found to upregulate CCL2 expression through the nuclear factor-κB pathway.
  • Analysis of human ESCC data revealed a subtype characterized by high CCL2 and CD274/PD-L1 expression, mirroring the PCN-knockout model.

Conclusions:

  • Loss of TP53, CDKN2A, and NOTCH1 is a key driver of ESCC initiation, promoting both neoplasia and immune evasion.
  • The study identifies a specific ESCC subtype associated with PCN gene alterations and immune evasion markers.
  • CCL2 blockade presents a potential therapeutic strategy for targeting this PCN-type ESCC.
Keywords:
CCL2CDKN2AEsophageal Squamous Cell CancerImmune EvasionImmunotherapyNOTCHOrganoidsPatient StratificationSingle-Cell RNA-SequencingTP53

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