PRMT7-specific PROTAC degrader achieves improved adoptive cancer immunotherapy by enhancing CD8+ T effector function through NF-kB activation.

New therapeutics are required to ameliorate cytotoxic T lymphocytes (CTL) for improved immunotherapy and T cell therapies. Herein we report that deletion of Prmt7 in T cells in mice with CD4-Cre increased CD8+ T effector cell cytokine production, cytolytic activity and anti-tumor activity of CTLs by transcriptional reprogramming. We show that Prmt7-deficiency in CTLs reprograms the CD8+ T cells with many transcription factors allowing them to exhibit increased proliferation, and express effector molecules. To translate these findings into a potential clinically applicable treatment, we generated a PRMT7 PROTAC degrader (MS54). We show that CTLs treated with the MS54 had similar reprogramming as the Prmt7 cKO CTLs. Adoptive cell transfer of MS54-treated CTLs from OT-I mice significantly enhanced their anti-tumor activity in a syngeneic melanoma murine cancer model. Human CTLs treated with the MS54 had increased proliferation, and enhanced activation markers. Our findings show that the MS54 has potential therapeutic utility for immunotherapy and adoptive cell therapy by reprogramming CTLs.