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

Abstract

Nuclear receptor coactivator 2 (Ncoa2) is a member of the Ncoa family of co-activators, 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-1α expression to enhance mitochondrial function. Mice deficient in Ncoa2 in T cells (Ncoa2fl/fl/CD4Cre) displayed defective immune responses against implanted MC38 tumors, which associated with significantly reduced tumor-infiltrating CD8+ T cells and decreased IFNγ production. Consistently, CD8+ T cells from Ncoa2fl/fl/CD4Cre mice failed to reject tumors after adoptive transfer into Rag1-/- mice. Further, in response to TCR stimulation, Ncoa2fl/fl/CD4Cre CD8+ T cells failed to increase mitochondrial mass, showed impaired oxidative phosphorylation, and had lower expression of PGC-1α, 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-1α expression. Forced expression of PGC-1α in Ncoa2fl/fl/CD4Cre CD8+ T cells restored mitochondrial function, T-cell activation, IFNγ production, and anti-tumor immunity. This work informs the development of Ncoa2-based therapies that modulate CD8+ T cell-mediated anti-tumor immune responses.

Population Structure and Selection Signal Analysis of Nanyang Cattle Based on Whole-Genome Sequencing Data

“…In our study of the NY cattle population, we identified genes associated with immunity ( NCOA2 , HSF1 , and PAX5 ). NCOA2 , a member of the nuclear receptor coactivator family, was found by Zhong et al [ 37 ] to stimulate T-cell activation and enhance mitochondrial function by upregulating the expression of PGC-1α , thereby promoting T-cell-mediated immune response. Additionally, Zhang et al [ 31 ] demonstrated in a mouse study that the overexpression of HSF1 reduces apoptosis of islet β cells by enhancing the expression of SIRPα.…”

Mitochondrial quality control in human health and disease

“…As the principal effectors of anti-tumor immunity, functional cytotoxic CD8 + T cells are closely related to the survival of cancer patients [ 332 , 333 ]. Naïve CD8 + T cells maintain their low metabolic demands by relying on OXPHOS; while the T cell receptor (TCR) is activated, metabolic reprogramming occurs in effector T cells, including aerobic glycolysis, OXPHOS, and glutaminolysis to meet the requirements of proliferative outbreak and effector functions [ 332 , 334 ].…”

“…Experiments have demonstrated that the TME can impair PGC-1α-mediated mitochondrial biogenesis and function in tumor-infiltrating CD8 + T cells, in part by chronic activation of Akt, and these processes can be reversed by PGC-1α overexpression [ 336 ]. In addition, nuclear receptor coactivator 2 has also been proven to be an upstream factor in the promotion of PGC-1α expression, which is involved in the regulation of CD8 + T cell-mediated anti-tumor immune responses [ 333 ]. Malinee et al [ 337 ] reported that EnPGC-1, an epigenetic activator of PGC-1α/β, enhances mitochondrial biogenesis and increases OXPHOS and FAO in effector T cells, improving the synergistic effect of PD-1 blockade therapy.…”

Fueling CARs: metabolic strategies to enhance CAR T-cell therapy

“…It is essential to keep in mind that PGC-1α is a crucial modulator in mitochondrial biogenesis. PGC-1α activates the NRF1/2-TFAM axis to stimulate mitochondrial DNA replication and transcription, thereby increasing mitochondrial content [ 52 – 55 ]. Not only AMPK, but also the PI3K/Akt/mTOR-axis contributes to the regulation of PGC-1α [ 56 ].…”

“…Not only AMPK, but also the PI3K/Akt/mTOR-axis contributes to the regulation of PGC-1α [ 56 ]. Studies have shown that exhausted T cells experience progressive loss of PGC-1α due to PD-1-mediated Akt signaling, while overexpression of PGC-1α enhances mitochondrial activity, persistence, memory formation; resulting in improved in vivo efficacy [ 54 , 55 , 57 ].…”