CD96 Is an Immune Checkpoint That Regulates CD8⁺ T-cell Antitumor Function

Area of Science:

• Immunology
• Cancer Research
• Molecular Biology

Background:

• CD96 regulates NK cell function and metastasis.
• CD96's role in T cell-mediated antitumor immunity is emerging.

Purpose of the Study:

• To investigate CD96 as a target for cancer immunotherapy.
• To evaluate the efficacy of blocking CD96, alone and in combination with other immune checkpoint inhibitors.

Main Methods:

• Experimental mouse tumor models.
• mRNA analysis, flow cytometry, and multiplex immunohistofluorescence (IHF).
• Assessment of CD8+ T cell-dependent antitumor activity.

Main Results:

• Blocking CD96 suppressed primary tumor growth in a CD8+ T cell-dependent manner.
• Anti-CD96 therapy was effective in combination with PD-1, PD-L1, TIGIT, and CTLA-4 blockade.
• Coexpression of PD-1 and CD96 was observed on CD8+ T cells in human and mouse tumors.
• Combination therapy increased IFNγ-expressing CD8+ T cells and superior antitumor responses.

Conclusions:

• CD96 functions as an immune checkpoint on CD8+ T cells.
• Blocking CD96 enhances T cell activity and tumor suppression.
• Combination therapy targeting CD96 with other immune checkpoint inhibitors is a promising cancer immunotherapy strategy.