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Secreted PTEN binds PLXDC2 on macrophages to drive antitumor immunity and tumor suppression

Cheng Zhang1, Hong-Ming Ma2, Shuai Wu3

  • 1Institute of Aging & Tissue Regeneration, Stress and Cancer Research Unit of Chinese Academy of Medical Sciences (No.2019RU043), State Key Laboratory of Systems Medicine for Cancer, Ren-Ji Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200127, China; School of Basic Medicine and Life Science, Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, Hainan 571199, China.

Developmental Cell
|August 28, 2024
PubMed

Insights

Loss of phosphatase and tensin homolog (PTEN) can be secreted, acting like a cytokine to boost antitumor immunity. Extracellular PTEN protein therapy enhances immune cell activity and suppresses tumor growth, offering new cancer treatment potential.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Loss of phosphatase and tensin homolog (PTEN) is associated with an immunosuppressive tumor microenvironment.
  • The mechanisms by which PTEN influences tumor immunity are not fully understood.

Purpose of the Study:

  • To investigate the role of secreted PTEN in regulating the tumor microenvironment and antitumor immunity.
  • To explore the therapeutic potential of extracellular PTEN administration in cancer immunotherapy.

Main Methods:

  • Investigated PTEN secretion via the TMED10 pathway.
  • Administered PTEN protein intratumorally in mouse models.
  • Analyzed macrophage phenotype switching and immune cell activation (CD8+ T cells, NK cells).
  • Assessed the efficacy of PTEN treatment in combination with anti-PD-1 therapy.

Main Results:

  • PTEN is secreted through the TMED10 pathway; inhibiting secretion promotes immunosuppression.
  • Extracellular PTEN binds PLXDC2 on macrophages, activating JAK2-STAT1 signaling.
  • This switches TAMs to an inflammatory phenotype, enhancing CD8+ T and NK cell activity.
  • PTEN treatment suppressed tumor growth, improved anti-PD-1 efficacy, and reversed immunosuppressive TAM phenotypes.

Conclusions:

  • PTEN functions as a cytokine-like molecule that activates antitumor immunity.
  • Extracellular PTEN administration demonstrates significant therapeutic potential for cancer immunotherapy.
Keywords:
JAK2PLXDC2PTENTMED10antitumor immunitymacrophagesunconventional protein secretion

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