Suppression of Metastases Using a New Lymphocyte Checkpoint Target for Cancer Immunotherapy

Area of Science:

• Immunology
• Cancer Biology
• Immunotherapy

Background:

• CD96 negatively regulates natural killer (NK) cell activity.
• Mice lacking CD96 exhibit hyperresponsive NK cells during immune challenges.

Purpose of the Study:

• To investigate the antimetastatic potential of blocking CD96 using a monoclonal antibody.
• To elucidate the mechanisms underlying the antimetastatic effects of anti-CD96 therapy.

Main Methods:

• Utilized three distinct tumor models to assess the efficacy of anti-CD96 antibody.
• Investigated the role of NK cells, CD226 (DNAM-1), IFNγ, and Fc receptors in anti-CD96 activity.
• Evaluated combination therapies including anti-CTLA-4, anti-PD-1, and doxorubicin chemotherapy.
• Assessed the impact of CD96 blockade in Tigit(-/-) mice.

Main Results:

• Anti-CD96 antibody treatment significantly inhibited experimental metastases in tested tumor models.
• The antimetastatic effect was dependent on NK cells, CD226, and IFNγ, but not activating Fc receptors.
• Combination of anti-CD96 with anti-CTLA-4, anti-PD-1, or doxorubicin enhanced antimetastatic activity.
• Blocking CD96 in Tigit(-/-) mice further reduced experimental and spontaneous metastases.
• Co-blockade of CD96 and PD-1 potently inhibited lung metastases, increasing NK-cell infiltration and IFNγ production.

Conclusions:

• Blocking the CD96-CD155 interaction with an antibody stimulates NK-cell function and exhibits antimetastatic activity.
• Targeting host CD96 represents a novel and complementary immunotherapeutic strategy for reducing tumor metastasis.
• CD96 blockade complements surgery and conventional immune checkpoint inhibitors.