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Programmed Death Ligand-1 in Melanoma and Extracellular Vesicles Promotes Local and Regional Immune Suppression

Lili Huang1, Jingbo Yang2, Jinjin Zhu1

  • 1Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

The American Journal of Pathology
|October 31, 2024
PubMed

Insights

Programmed death-ligand 1 (PD-L1) in melanoma cells drives M2-like macrophage polarization and immune suppression. PD-L1 knockout in melanoma decelerates tumor growth and enhances anti-tumor immunity.

Area of Science:

  • Immunology
  • Oncology
  • Cancer Research

Background:

  • Tumor-associated macrophages (TAMs) exhibit dual roles in tumor progression.
  • TAMs can induce programmed death-ligand 1 (PD-L1) expression in cancer cells.
  • The influence of melanoma PD-L1 on TAM polarization is not well understood.

Purpose of the Study:

  • Investigate the role of PD-L1 in melanoma cells on TAM phenotypical switching.
  • Determine the impact of PD-L1 knockout in melanoma on tumor growth and immune cell infiltration.
  • Elucidate the mechanisms by which melanoma PD-L1 and its extracellular vesicles (EVs) affect the tumor microenvironment.

Main Methods:

  • PD-L1 knockout (PD-L1KO) in YUMM1.7 and B16-F10 melanoma cell lines.
  • In vivo tumor growth rate assessment in mice.
  • Flow cytometry analysis of immune cell populations (M1/M2 macrophages, dendritic cells, CD8+ T cells).
  • Analysis of chemokine and cytokine expression.
  • Treatment with extracellular vesicles (EVs) derived from PD-L1KO and wild-type (WT) melanoma cells.

Main Results:

  • Elevated CD163 and MRC1 levels in metastatic melanomas correlated with CD274 (PD-L1) expression.
  • PD-L1KO melanoma exhibited decelerated in vivo growth, increased M1/M2 ratio, more dendritic cells, and enhanced CD8+ T cell activation.
  • PD-L1KO tumors showed decreased M2-associated chemokines and cytokines.
  • Mice with PD-L1KO melanomas had higher levels of CD8+ T cells in lymph nodes and blood.
  • EVs from PD-L1KO melanoma reduced tumor growth and M2-like macrophage infiltration.

Conclusions:

  • Melanoma PD-L1 and melanoma-derived EVs promote M2-like macrophage polarization.
  • This polarization contributes to local and regional immune suppression in melanoma.
  • Targeting PD-L1 in melanoma may represent a therapeutic strategy to enhance anti-tumor immunity.

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