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Antagonizing Integrin β3 Increases Immunosuppression in Cancer

Xinming Su1, Alison K Esser1, Sarah R Amend1

  • 1Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.

Cancer Research
|May 25, 2016
PubMed

Insights

Integrin β3 antagonists may worsen cancer by promoting M2 macrophages and reducing CD8(+) T cells. Targeting integrin β3 in immune cells could improve cancer therapy outcomes.

Area of Science:

  • Immunology
  • Oncology
  • Cell Biology

Background:

  • Integrin β3 is a target for cancer therapy due to its role in tumor invasion, angiogenesis, and inflammation.
  • Previous studies on integrin β3 antagonists have yielded disappointing or negative clinical results.

Purpose of the Study:

  • To investigate the role of integrin β3 in tumor immunity.
  • To determine the impact of integrin β3 deletion in macrophages on cancer progression.
  • To evaluate the effects of integrin β3 antagonism on the tumor immune microenvironment.

Main Methods:

  • Generated mice with integrin β3 deleted in macrophage lineage cells (β3KOM).
  • Assessed tumor growth, immune cell infiltration (M2 macrophages, CD8(+) T cells), and signaling pathways (STAT1, STAT6) in mouse models.
  • Administered integrin β3 antagonist cilengitide to evaluate its effects on tumor growth and immunity.

Main Results:

  • β3KOM mice exhibited increased melanoma and breast cancer growth, characterized by more M2 macrophages and fewer CD8(+) T cells.
  • Cilengitide treatment also enhanced tumor growth and M2 macrophage function.
  • Integrin β3 signaling was found to promote M1 polarization (via STAT1) and suppress M2 polarization (via STAT6) in M2 myeloid cells.
  • Disrupting CD8(+) T cells, macrophages, or macrophage integrin β3 signaling counteracted the tumor-promoting effects of integrin β3 antagonism.

Conclusions:

  • Integrin β3 plays a crucial role in regulating the tumor immune microenvironment.
  • Integrin β3 antagonism can promote tumor growth by altering macrophage polarization and T cell responses.
  • Considering the impact of integrin β3 therapies on immune cells is essential for improving cancer treatment outcomes.

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