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Targeting a cell surface vitamin D receptor on tumor-associated macrophages in triple-negative breast cancer

Fernanda I Staquicini1,2, Amin Hajitou3, Wouter Hp Driessen4

  • 1Rutgers Cancer Institute of New Jersey, Newark, United States.

Elife
|June 1, 2021
PubMed

Insights

Researchers discovered a peptide targeting tumor-associated macrophages in triple-negative breast cancer (TNBC). This peptide CSSTRESAC targets PDIA3, enhances antitumor immunity, and could offer new therapeutic strategies for TNBC.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Triple-negative breast cancer (TNBC) presents significant therapeutic challenges due to its aggressive nature and limited treatment options.
  • The immunosuppressive tumor microenvironment in TNBC contributes to poor patient prognosis.
  • Targeting non-malignant cells within the tumor microenvironment is a promising strategy for cancer therapy.

Purpose of the Study:

  • To identify novel peptides that specifically target the immunosuppressive cellular microenvironment of TNBC.
  • To explore the therapeutic potential of identified peptides in preclinical models of breast cancer.
  • To investigate the role of PDIA3-expressing tumor-associated macrophages (TAM) in TNBC and their interaction with the immune response.

Main Methods:

  • In vivo phage display technology was employed to isolate peptides with homing capabilities to the TNBC microenvironment.
  • A cyclic peptide, CSSTRESAC, was identified and characterized for its binding specificity to PDIA3 on TAM.
  • The efficacy of CSSTRESAC was evaluated in syngeneic, xenograft, and transgenic mouse models of breast cancer, including assessments of immune response and tumor growth.
  • Ligand-directed theranostic delivery and in silico analysis of patient data were utilized.

Main Results:

  • CSSTRESAC specifically binds to PDIA3, a cell surface receptor on TAM.
  • Systemic administration of CSSTRESAC modulated the cytokine profile towards an antitumor immune response in TNBC models.
  • CSSTRESAC treatment resulted in delayed tumor growth in preclinical models.
  • In silico analysis confirmed the presence of PDIA3-expressing TAM in human TNBC samples.

Conclusions:

  • The study identifies a functional interplay between cell surface PDIA3 on TAM and the antitumor immune response in TNBC.
  • CSSTRESAC demonstrates potential as a therapeutic agent and a theranostic tool for TNBC.
  • Targeting PDIA3 on TAM represents a viable strategy for developing novel immunotherapies for triple-negative breast cancer.
Keywords:
medicinemousetriple-negative breast cancertumor-associated macrophagevitamin D receptor

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