ASCL2 Affects the Efficacy of Immunotherapy in Colon Adenocarcinoma Based on Single-Cell RNA Sequencing Analysis

Front Immunol. 2022 Jun 3;13:829640. doi: 10.3389/fimmu.2022.829640. eCollection 2022.

Abstract

Colon adenocarcinoma (COAD) is one of the leading causes of cancer-associated deaths worldwide. Patients with microsatellite instability-high (MSI-H) tumors were shown to highly benefit from immune checkpoint inhibitors (ICIs) than patients with microsatellite stable (MSS) tumors. Furthermore, the infiltration of immune cells and the expression of cancer stem cells (CSCs) in COAD were associated with the anti-tumor immune response. However, the potential mechanisms showing the relationship between microsatellite instability and CSCs or tumor-infiltrating immune cells (TIICs) have not been elucidated. Accumulating evidence reveals that achaete-scute family bHLH transcription factor 2 (ASCL2) plays a crucial role in the initiation and progression of COAD and drug resistance. However, the specific biological functions of ASCL2 in COAD remain unknown. In this study, we performed weighted gene co-expression network analysis (WGCNA) between MSS and MSI-H subsets of COAD. The results revealed that ASCL2 was a potential key candidate in COAD. Subsequently, the single-cell RNA-seq revealed that ASCL2 was positively associated with CSCs. Further, ASCL2 was shown to indirectly affect tumor immune cell infiltration by negatively regulating the expression of DUSP4. Finally, we inferred that the immunotherapy-sensitive role of ASCL2/DUSP4 axis on COAD is partly attributed to the activation of WNT/β-catenin pathway. In conclusion, this study revealed that ASCL2 was positively correlated to CSCs and tumor immune infiltration in COAD. Therefore, ASCL2 is a promising predictor of clinical responsiveness to anti-PD-1/PD-L1 therapy in COAD.

Keywords: colon adenocarcinoma; immunotherapy; microsatellite instability-high; microsatellite stable; single-cell RNA-seq.

MeSH terms

  • Adenocarcinoma* / genetics
  • Adenocarcinoma* / metabolism
  • Adenocarcinoma* / therapy
  • Basic Helix-Loop-Helix Transcription Factors* / genetics
  • Basic Helix-Loop-Helix Transcription Factors* / metabolism
  • Colonic Neoplasms* / genetics
  • Colonic Neoplasms* / metabolism
  • Colonic Neoplasms* / therapy
  • Humans
  • Immunotherapy
  • Microsatellite Instability
  • Sequence Analysis, RNA

Substances

  • ASCL2 protein, human
  • Basic Helix-Loop-Helix Transcription Factors