Cabozantinib Eradicates Advanced Murine Prostate Cancer by Activating Antitumor Innate Immunity

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Kinase inhibitors are used in cancer therapy, but their effects on the tumor immune microenvironment are not well understood.
• Cabozantinib is a tyrosine kinase inhibitor that has shown promising responses in clinical trials across various cancers.
• The precise mechanisms by which cabozantinib exerts its antitumor effects, particularly regarding immune system activation, require further investigation.

Purpose of the Study:

• To investigate the impact of cabozantinib on the tumor immune microenvironment.
• To elucidate the mechanisms underlying cabozantinib's efficacy in preclinical cancer models.
• To determine if cabozantinib can activate innate immune responses against cancer cells.

Main Methods:

• Utilized PTEN/p53-deficient murine prostate cancer models.
• Administered cabozantinib and assessed tumor eradication.
• Analyzed the release of neutrophil chemotactic factors (CXCL12, HMGB1) from tumor cells.
• Investigated the role of neutrophils in tumor clearance using antibody-mediated granulocyte depletion and CXCR4 inhibition (plerixafor).

Main Results:

• Cabozantinib rapidly eradicated invasive, poorly differentiated PTEN/p53-deficient murine prostate cancer.
• Tumor eradication was associated with increased release of CXCL12 and HMGB1, leading to neutrophil infiltration.
• Depletion of neutrophils, HMGB1 neutralization, or blockade of neutrophil chemotaxis abrogated cabozantinib's tumor-clearing effects.

Conclusions:

• Cabozantinib activates a neutrophil-mediated innate immune response against invasive prostate cancer.
• The study demonstrates a novel mechanism where a tyrosine kinase inhibitor enhances antitumor immunity via neutrophils.
• These findings suggest potential therapeutic strategies combining kinase inhibitors with immunomodulatory approaches for cancer treatment.