Impact of Sirt2 deficiency on downstream TCR signaling in mouse melanoma tumor-infiltrating T lymphocytes

The T-cell receptor (TCR) signaling pathway is a highly regulated system designed to prevent autoimmunity while ensuring effective immune responses. This regulation is typically mediated through phosphorylation, dephosphorylation, and ubiquitination. Sirt2, is a cytoplasmic NAD+-dependent histone deacetylase with anti-aging and antioxidant properties. Here we reveal acetylation modulated by Sirt2 as a previously unrecognized process controlling TCR signaling. In our study, we found that the loss of Sirt2 in T cells leads to enhanced TCR signaling following T cell activation. Furthermore, we demonstrated that inhibiting Sirt2 in both murine and human tumor-infiltrating lymphocytes restores TCR responsiveness and enhances their anti-tumor activity. This suggests Sirt2 targeting as a potential therapeutic approach for reactivating exhausted T cells within the tumor microenvironment. Overall design: To investigate the impact of Sirt2 deficiency on pathways downstream of T-cell receptor (TCR) signaling within the tumor microenvironment, we conducted RNA sequencing analysis on tumor-infiltrating T lymphocytes from wild-type and Sirt2 knockout mice bearing B16F10 subcutaneous tumors.