Ncoa2 Promotes CD8+ T cell-Mediated Antitumor Immunity by Stimulating T-cell Activation via Upregulation of PGC-1α Critical for Mitochondrial Function

Nuclear receptor coactivator 2 (Ncoa2) is a member of the Ncoa family of coactivators, and we previously showed that Ncoa2 regulates the differentiation of induced regulatory T cells. However, it remains unknown if Ncoa2 plays a role in CD8(+) T-cell function. Here, we show that Ncoa2 promotes CD8(+) T cell-mediated immune responses against tumors by stimulating T-cell activation via upregulating PGC-1 alpha expression to enhance mitochondrial function. Mice deficient in Ncoa2 in T cells (Ncoa2(fl/fl)/CD4(Cre)) displayed defective immune responses against implanted MC38 tumors, which associated with significantly reduced tumor-infiltrating CD8(+) T cells and decreased IFN gamma production. Consistently, CD8(+) T cells from Ncoa2(fl/fl)/CD4(Cre) mice failed to reject tumors after adoptive transfer into Rag1(-/-) mice. Further, in response to TCR stimulation, Ncoa2(fl/fl)/CD4(Cre) CD8(+) T cells failed to increase mitochondrial mass, showed impaired oxidative phosphorylation, and had lower expression of PGC-1 alpha, a master regulator of mitochondrial biogenesis and function. Mechanically, T-cell activation-induced phosphorylation of CREB triggered the recruitment of Ncoa2 to bind to enhancers, thus, stimulating PGC-1 alpha expression. Forced expression of PGC-1 alpha in Ncoa2(fl/fl)/CD4Cre CD8(+) T cells restored mitochondrial function, T-cell activation, IFN gamma production, and antitumor immunity. This work informs the development of Ncoa2-based therapies that modulate CD8(+) T cell-mediated antitumor immune responses.(c) 2023 American Association for Cancer Research.