Innovative strategies to optimise colorectal cancer immunotherapy through molecular mechanism insights

Front Immunol. 2024 Dec 9:15:1509658. doi: 10.3389/fimmu.2024.1509658. eCollection 2024.

Abstract

Background: Colorectal cancer (CRC) is a leading cause of cancer-related deaths globally. The heterogeneity of the tumor microenvironment significantly influences patient prognosis, while the diversity of tumor cells shapes its unique characteristics. A comprehensive analysis of the molecular profile of tumor cells is crucial for identifying novel molecular targets for drug sensitivity analysis and for uncovering the pathophysiological mechanisms underlying CRC.

Methods: We utilized single-cell RNA sequencing technology to analyze 13 tissue samples from 4 CRC patients, identifying key cell types within the tumor microenvironment. Intercellular communication was assessed using CellChat, and a risk score model was developed based on eight prognostic genes to enhance patient stratification for immunotherapeutic approaches. Additionally, in vitro experiments were performed on DLX2, a gene strongly associated with poor prognosis, to validate its potential role as a therapeutic target in CRC progression.

Results: Eight major cell types were identified across the tissue samples. Within the tumor cell population, seven distinct subtypes were recognized, with the C0 FXYD5+ tumor cells subtype being significantly linked to cancer progression and poor prognosis. CellChat analysis indicated extensive communication among tumor cells, fibroblasts, and immune cells, underscoring the complexity of the tumor microenvironment. The risk score model demonstrated high accuracy in predicting 1-, 3-, and 5-year survival rates in CRC patients. Enrichment analysis revealed that the C0 FXYD5+ tumor cell subtype exhibited increased energy metabolism, protein synthesis, and oxidative phosphorylation, contributing to its aggressive behavior. In vitro experiments confirmed DLX2 as a critical gene associated with poor prognosis, suggesting its viability as a target for improving drug sensitivity.

Conclusion: In summary, this study advances our understanding of CRC progression by identifying critical tumor subtypes, molecular pathways, and prognostic markers that can inform innovative strategies for predicting and enhancing drug sensitivity. These findings hold promise for optimizing immunotherapeutic approaches and developing new targeted therapies, ultimately aiming to improve patient outcomes in CRC.

Keywords: FXYD5+ Tumor Risk Score (FTRS); colorectal cancer (CRC); energy metabolism in cancer; single-cell RNA sequencing (scRNA-seq); tumor cell subtypes.

MeSH terms

  • Biomarkers, Tumor / genetics
  • Cell Line, Tumor
  • Colorectal Neoplasms* / genetics
  • Colorectal Neoplasms* / immunology
  • Colorectal Neoplasms* / therapy
  • Female
  • Gene Expression Regulation, Neoplastic
  • Homeodomain Proteins* / genetics
  • Homeodomain Proteins* / metabolism
  • Humans
  • Immunotherapy* / methods
  • Male
  • Middle Aged
  • Prognosis
  • Single-Cell Analysis
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Microenvironment* / immunology

Substances

  • Homeodomain Proteins
  • Transcription Factors
  • Biomarkers, Tumor
  • Distal-less homeobox proteins

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was qualified by Shanghai Municipal Science and Technology Commission (20ZR1451700), and Shanghai Collaborative Innovation Center for Translational Medicine (TM201731). Research Fund for Key Subject Construction Project of Shanghai Municipal Health Commission (Gastrointestinal Surgery, No. ZK2019A15), and the Research Fund of Shanghai Tongren Hospital, Shanghai Jiaotong University School of Medicine.