Ncoa2 promotes CD8+ T cell-mediated anti-tumor 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 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.

Citation

Xiancai Zhong, Hongmin Wu, Ching Ouyang, Wencan Zhang, Yun Shi, Yi-Chang Wang, David K Ann, Yousang Gwack, Weirong Shang, Zuoming Sun. Ncoa2 promotes CD8+ T cell-mediated anti-tumor immunity by stimulating T-cell activation via upregulation of PGC-1α critical for mitochondrial function. Cancer immunology research. 2023 Aug 04

PMID: 37540802

search → result