Cancer ATF4-mediated CD58 endocytosis impairs anti-tumor immunity and immunotherapy

Area of Science:

• Immunology
• Cancer Biology
• Molecular Biology

Background:

• Co-stimulatory molecules are crucial for CD8+ T cell-mediated tumor elimination.
• Tumor cell-intrinsic mechanisms regulating co-stimulatory molecules are not fully understood.
• Understanding these mechanisms could improve cancer treatment strategies.

Purpose of the Study:

• To investigate the role of tumor cell-intrinsic factors in regulating co-stimulatory molecule expression.
• To elucidate the mechanism by which tumor cells downregulate CD58.
• To identify potential therapeutic targets for enhancing anti-tumor immunity.

Main Methods:

• Investigated the role of ATF4 in CD58 regulation in tumor cells.
• Utilized techniques to assess immunological synapse formation and CD8+ T cell cytotoxicity.
• Examined the effect of ATF4 knockdown and DDE inhibitors on CD58 expression and anti-tumor responses.

Main Results:

• Tumor cell expression of ATF4 leads to decreased CD58 levels.
• ATF4 upregulates dynamin 1 (DNM1), promoting CD58 degradation via DNM1-dependent endocytosis (DDE).
• Inhibition of DDE (using prochlorperazine) or ATF4 knockdown restored CD58 expression and enhanced CD8+ T cell cytotoxicity and immunotherapy efficacy.

Conclusions:

• Tumor cell ATF4 downregulates CD58, hindering immunological synapse formation and impairing CD8+ T cell anti-tumor function.
• Targeting ATF4 or DDE presents a promising strategy to enhance CD8+ T cell-mediated tumor immunotherapy.