EZH2 Inhibition Compromises α4-1BB-Mediated Antitumor Efficacy by Reducing the Survival and Effector Programming of...

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Enhancer of Zeste Homolog 2 (EZH2) inhibitors are approved cancer therapeutics.
• Combinations of EZH2 inhibitors with immune checkpoint inhibitors (e.g., PD-(L)1, CTLA-4) are being explored.
• The impact of EZH2 inhibition on therapies targeting T cell costimulatory receptors remains unknown.

Purpose of the Study:

• To investigate the efficacy of combining EZH2 inhibitors with 4-1BB agonist antibodies.
• To elucidate the mechanisms by which EZH2 inhibition affects 4-1BB-mediated T cell responses.

Main Methods:

• Utilized CT26 colon carcinoma and an in vivo protein immunization model.
• Administered EZH2 inhibitors in combination with alpha-4-1BB agonist antibodies.
• Analyzed CD8+ T cell populations, effector survival, and BIM expression.

Main Results:

• EZH2 inhibition significantly compromised the efficacy of alpha-4-1BB agonist antibodies.
• EZH2 inhibition led to reduced effector CD8+ T cell survival.
• Increased BIM expression was observed in CD8+ T cells treated with EZH2 inhibitors.

Conclusions:

• EZH2 is required for optimal 4-1BB-mediated CD8+ T cell expansion and effector programming.
• Combining EZH2 inhibitors with 4-1BB agonists may be detrimental to anti-tumor immunity.
• Careful consideration is needed when developing combination therapies involving EZH2 inhibitors and costimulatory receptor agonists.