PD-1-Positive Tumor-Associated Macrophages Define Poor Clinical Outcomes in Patients With Muscle Invasive Bladder...

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• Tumor-associated macrophages (TAMs) play a critical role in regulating tumor immunity.
• Programmed cell death protein 1 (PD-1)-positive TAMs exhibit an M2 macrophage phenotype.
• CD68 is a known biomarker for TAMs and a negative prognostic indicator in various cancers.

Purpose of the Study:

• To investigate the prognostic significance of PD-1-positive TAMs in muscle-invasive bladder cancer (MIBC).
• To elucidate the mechanistic link between CD68, PD-1, and M2 macrophage polarization in bladder cancer.
• To explore the therapeutic potential of targeting the CD68/PD-1 axis.

Main Methods:

• Analysis of immune cell types and clinical outcomes in 402 MIBC patients from TCGA database.
• Immunohistochemical analysis of PD-1-positive TAMs in 120 MIBC patient samples.
• Co-immunoprecipitation assays to determine CD68-PD-1 binding and in vitro studies using THP-1 derived macrophages and T24 bladder cancer cells.

Main Results:

• High immune score and M2 TAMs were associated with poor clinical outcomes in MIBC.
• PD-1-positive TAMs correlated with reduced 5-year overall and disease-free survival, increased PD-L1 expression, higher Ki67 index, advanced pT stage, and fewer CD8-positive T cells.
• CD68 binding to PD-1 induced M2 polarization and promoted cancer growth; anti-CD68 treatment combined with PBMCs inhibited T24 cell proliferation.

Conclusions:

• PD-1-positive TAMs are a negative prognostic indicator in MIBC.
• The interaction between CD68 and PD-1 drives M2 polarization and facilitates bladder cancer progression.
• The CD68/PD-1 axis represents a novel and promising therapeutic target for MIBC prognosis and treatment.