Intercellular Molecular Crosstalk Networks within Invasive and Immunosuppressive Tumor Microenvironment Subtypes...

Area of Science:

• Oncology
• Immunology
• Bioinformatics

Background:

• Tumor microenvironment (TME) heterogeneity is crucial for cancer progression.
• Understanding specific tumor microenvironment subtypes (subTMEs) at a single-cell level is essential for cancer research.
• Current knowledge lacks detailed characterization of subTME functions in cancer progression.

Purpose of the Study:

• To analyze single-cell RNA sequencing data to identify and characterize distinct subTMEs in breast, colorectal, esophageal, and pancreatic cancers.
• To investigate the cellular and molecular interactions within identified subTMEs and their association with cancer progression, invasion, and immune escape.
• To identify potential prognostic markers and therapeutic targets based on subTME characteristics.

Main Methods:

• Single-cell RNA sequencing analysis of 250 clinical samples across four cancer types.
• Construction of an intercellular infiltration model and unsupervised clustering to define subTMEs.
• Gene expression analysis (cytokines, chemokines, PD1, PD-L1), Cox regression modeling, and cell-cell interaction analysis.
• Validation using spatial transcriptome data from colorectal cancer samples.

Main Results:

• Four to five distinct subTMEs were identified in each cancer type.
• Immune-suppressive (subTME-IS) and matrix remodeling (subTME-MRM) subTMEs were enriched in tumors.
• Specific ligand-receptor interactions (e.g., COL1A1-SDC1, C5AR1-RPS19) were associated with tumor invasion, poor prognosis, and immune suppression.
• Upregulation of immune-related genes and specific markers like PDCD1 and TGFB1 in tumor-derived cells and subTME-IS was observed.

Conclusions:

• The study highlights significant heterogeneity within the TME, with distinct subTMEs exhibiting pro-invasion and pro-immunosuppressive functions.
• Identified key cellular and molecular interactions within subTMEs are associated with cancer survival, invasion, immune escape, and patient classification.
• These findings provide insights into the functional roles of subTMEs and suggest potential targets for cancer therapy and prognosis.