An inflammation-related subtype classification for analyzing tumor microenvironment and clinical prognosis in colorectal cancer

Front Immunol. 2024 Apr 29:15:1369726. doi: 10.3389/fimmu.2024.1369726. eCollection 2024.

Abstract

Background: The inflammatory response plays an essential role in the tumor microenvironment (TME) of colorectal cancer (CRC) by modulating tumor growth, progression, and response to therapy through the recruitment of immune cells, production of cytokines, and activation of signaling pathways. However, the molecular subtypes and risk score prognostic model based on inflammatory response remain to be further explored.

Methods: Inflammation-related genes were collected from the molecular signature database and molecular subtypes were identified using nonnegative matrix factorization based on the TCGA cohort. We compared the clinicopathological features, immune infiltration, somatic mutation profile, survival prognosis, and drug sensitivity between the subtypes. The risk score model was developed using LASSO and multivariate Cox regression in the TCGA cohort. The above results were independently validated in the GEO cohort. Moreover, we explored the biological functions of the hub gene, receptor interacting protein kinase 2 (RIPK2), leveraging proteomics data, in vivo, and in vitro experiments.

Results: We identified two inflammation-related subtypes (inflammation-low and inflammation-high) and have excellent internal consistency and stability. Inflammation-high subtype showed higher immune cell infiltration and increased sensitivity to common chemotherapeutic drugs, while inflammation-low subtype may be more suitable for immunotherapy. Besides, the two subtypes differ significantly in pathway enrichment and biological functions. In addition, the 11-gene signature prognostic model constructed from inflammation-related genes showed strong prognostic assessment power and could serve as a novel prognostic marker to predict the survival of CRC patients. Finally, RIPK2 plays a crucial role in promoting malignant proliferation of CRC cell validated by experiment.

Conclusions: This study provides new insights into the heterogeneity of CRC and provides novel opportunities for treatment development and clinical decision making.

Keywords: colorectal cancer; inflammatory response; molecular subtype; prognosis; tumor microenvironment.

MeSH terms

  • Animals
  • Biomarkers, Tumor
  • Cell Line, Tumor
  • Colorectal Neoplasms* / genetics
  • Colorectal Neoplasms* / immunology
  • Colorectal Neoplasms* / mortality
  • Colorectal Neoplasms* / pathology
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Inflammation* / immunology
  • Male
  • Mice
  • Prognosis
  • Transcriptome
  • Tumor Microenvironment* / immunology

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was funded in part by the Science Foundation of Peking University Cancer Hospital (PY202317) to JP. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.