An Immunotherapeutic CD137 Agonist Releases Eomesodermin from ThPOK Repression in CD4 T Cells

Area of Science:

• Immunology
• Cancer Immunology
• T cell biology

Background:

• Costimulatory receptors OX40 (CD134) and 4-1BB (CD137) agonists can elicit antitumor immunity.
• Dual costimulation with both OX40 and 4-1BB agonists is particularly potent, programming cytotoxic potential in both CD8+ and CD4+ T cells.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying the cytotoxic programming of CD4+ T cells induced by dual costimulation with OX40 and 4-1BB agonists.
• To investigate the roles of transcription factors eomesodermin (Eomes) and Runx3 in this process.

Main Methods:

• Investigated the induction of Eomes and Runx3 in CD4+ T cells following dual costimulation.
• Utilized knockout models (CD134-/-) to assess the necessity of each costimulatory pathway.
• Analyzed the interplay between ThPOK, Eomes, and Runx3 expression.

Main Results:

• Cytotoxicity in dual-costimulated CD4+ T cells depends on Eomes, induced independently of IL-2.
• Eomes induction relies on Runx3, a CD8+ T cell lineage commitment factor, which supports Eomes expression in CD8+ CTLs.
• Eomes and Runx3 are indispensable for the antitumor activity of dual-costimulated CD4+ T cells in a melanoma model.
• Dual costimulation induces Eomes in CD4+ T cells despite continued ThPOK expression, indicating selective release from repression.
• While CD137 agonist alone can induce Eomes, it fails to do so in CD134-/- CD4+ T cells, highlighting the requirement for both pathways.

Conclusions:

• Dual costimulation via OX40 and 4-1BB is crucial for programming cytotoxic CD4+ T cells.
• The transcription factors Runx3 and Eomes are key mediators of this cytotoxic programming.
• Both OX40 and 4-1BB costimulatory pathways are required for effective cytotoxic CD4+ T cell responses, even when targeting 4-1BB therapeutically.