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  11. Mesothelin Expression Correlates With Elevated Inhibitory Immune Activity In Patients With Colorectal Cancer

Mesothelin expression correlates with elevated inhibitory immune activity in patients with colorectal cancer

Midhun Malla1, Sachin Kumar Deshmukh2, Sharon Wu2

  • 1University of Alabama, Birmingham, AL, USA. midhunmalla@uabmc.edu.

Cancer Gene Therapy
|August 22, 2024

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View abstract on PubMed

Summary
This summary is machine-generated.

Mesothelin (MSLN) protein is highly expressed in aggressive colorectal cancer (CRC), particularly in microsatellite-stable (MSS) subtypes. High MSLN correlates with immune suppression and suggests MSLN as a potential therapeutic target for MSS CRC.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Colorectal cancer (CRC) is a leading cause of cancer death, with metastatic (mCRC) patients often developing treatment resistance.
  • Microsatellite-stable (MSS) CRC, prevalent in mCRC, is generally unresponsive to immunotherapy.
  • Mesothelin (MSLN) protein expression varies in cancers and is linked to aggressive disease and poor survival in CRC.

Purpose of the Study:

  • To characterize MSLN expression in CRC and its correlation with clinical outcomes.
  • To investigate the impact of MSLN on the tumor immune microenvironment in CRC.
  • To explore MSLN as a potential therapeutic target for high MSLN-expressing MSS CRC.

Main Methods:

  • Analysis of MSLN protein levels in CRC patient cohorts.
  • Correlation of MSLN expression with clinicopathological features and survival outcomes.

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  • Assessment of immune cell infiltration (macrophages), PD-L1 expression, and gene expression related to immune suppression and signaling pathways (e.g., TGF-β, IL6/JAK/STAT3).

    • Main Results:

    • Higher MSLN expression was observed in CMS1 and CMS4 CRC subtypes.
    • MSLN-high patients showed increased gene mutation rates.
    • Elevated M1/M2 macrophage infiltration, PD-L1 staining, and immune-inhibitory gene expression were noted in MSLN-high tumors.
    • Enrichment of inflammatory, TGF-β, IL6/JAK/STAT3, and IL2/STAT5 signaling pathways was associated with high MSLN.
    • Mutations in KRAS and FBXW7 were more frequent in MSLN-high patients.

    Conclusions:

    • MSLN protein is a potential target for antigen-specific therapies in CRC.
    • MSLN expression influences the immune microenvironment, promoting immune suppression.
    • Further research into MSLN's tumorigenic effects may reveal therapeutic strategies for high MSLN-expressing MSS CRC.