Mitochondrial transcription is essential for the potent antitumor stem memory T cells

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Presentation Time: 09:45 AM - 10:00 AM
Abstract ID: 4268 - B

Presenting Author:
Soundharya Kumaresan , Lead Research Specialist at Winship Cancer Inst., Emory Univ.

Abstract:

Adoptive T cell transfer (ACT) therapy is an effective approach to treat cancer patients, where expanding the patient’s T lymphocytes and redirecting them to recognize and regress solid tumors. Unfortunately, ACT can fail in some patients due to exhaustion or impaired metabolic fitness during T cell expansion. We discovered through transcriptomic analysis that the novel mitochondrial transcription regulator REXO2 induced by regulating PI3Kδ signaling in vitro - generated stem memory T cells (T_SCM) - is responsible for the antitumor potency of T_SCM cells. This finding is novel, as REXO2 has never been studied in immune cells and has only recently been appreciated in regulating heart muscles during embryonic development. We found that knocking out REXO2 via CRISPR in T_SCM cells impaired their mitochondrial transcription and morphology in vitro. Moreover, they had reduced metabolic fitness marked by poor spare respiratory capacity, reduced mitochondrial potential and increased production of reactive oxygen species post tumor antigen recognition. Of clinical importance, REXO2 knockout in T_SCM cells impaired the antitumor potency when infused into mice. This work also has translational potential, as REXO2 could be induced in human TIL or CAR T cell products by expanding them in the presence of PI3Kδ inhibitor. Our findings reveal that REXO2 is a promising target to bolster the antitumor activity of next generation TIL and CAR T cell products to treat cancer patients.