The Inhibitory Signaling Receptor Protocadherin-18 Regulates Tumor-Infiltrating CD8⁺ T-cell Function

Area of Science:

• Immunology
• Cancer Biology
• Molecular Biology

Background:

• CD8+ T cells are crucial for antitumor immunity but often become dysfunctional within the tumor microenvironment.
• Tumor-infiltrating lymphocytes (TILs) express inhibitory receptors (checkpoint inhibitors) that limit their effector functions.
• Protocadherin-18 was previously identified as a novel inhibitory signaling receptor on murine CD8+ TILs that abrogates T cell receptor (TCR) signaling.

Purpose of the Study:

• To investigate the role of protocadherin-18 in regulating CD8+ TIL effector function and antitumor activity.
• To evaluate the therapeutic potential of targeting protocadherin-18, alone or in combination with PD-1 blockade, for enhancing anti-cancer immunity.

Main Methods:

• Utilized genetically modified mice lacking protocadherin-18 to assess its impact on TILs.
• Administered combined blockade of PD-1 and protocadherin-18 in wild-type mice.
• Assessed antitumor activity and TIL effector phase function.

Main Results:

• Deletion of protocadherin-18 in mice led to enhanced CD8+ TIL antitumor activity.
• Combined blockade of PD-1 and protocadherin-18 significantly improved TIL effector function in wild-type mice.
• Protocadherin-18 plays a critical role in limiting antitumor T cell responses.

Conclusions:

• Protocadherin-18 acts as a key inhibitory receptor that dampens CD8+ TIL antitumor immunity.
• Targeting protocadherin-18, particularly in combination with PD-1 blockade, represents a promising strategy to reinvigorate anti-cancer T cell responses.