TMED inhibition suppresses cell surface PD-1 expression and overcomes T cell dysfunction

Area of Science:

• Immunology
• Cancer Biology
• Molecular Biology

Background:

• Programmed cell death protein 1 (PD-1) immune checkpoint blockade (ICB) is a promising cancer therapy.
• Mechanisms regulating PD-1 expression on CD8 T cells remain largely unknown.
• PD-1 is induced upon T cell activation, necessitating identification of regulators that suppress PD-1 without impairing T cell function.

Purpose of the Study:

• To uncover novel regulators of PD-1 expression on CD8 T cells.
• To identify targets for enhancing anti-tumor immune responses.
• To find regulators whose inhibition reduces PD-1 abundance without compromising T cell activation.

Main Methods:

• A whole-genome CRISPR-Cas9 screen was performed on primary murine CD8 T cells.
• A dual-readout system using CD137 as an activation marker distinguished PD-1 regulators from general T cell activation genes.
• In vitro and in vivo experiments utilized TMED inhibitors and analysis of tumor-infiltrating lymphocytes (TILs).

Main Results:

• Inactivation of TMED family proteins, particularly TMED10, reduced PD-1 surface abundance and enhanced T cell activity.
• TMED inactivation also suppressed cytotoxic T lymphocyte-associated protein 4 (CTLA-4) expression.
• TMED inhibitor treatment led to lysosomal degradation of TMED-PD-1 complexes, reduced PD-1 in tumor-infiltrating CD8 T cells, and reversed T cell dysfunction.
• High TMED expression in CD8 TILs correlated with T cell dysfunction signatures, poor ICB response, and shorter patient survival.

Conclusions:

• TMED family proteins represent a novel regulatory mechanism for PD-1 expression.
• TMED is identified as a pharmacologically tractable target for suppressing PD-1 and T cell dysfunction.
• Inhibition of TMED holds potential for improving cancer immunotherapy efficacy.