Anti-neoplastic sulfonamides alter the metabolic homeostasis and disrupt the suppressor activity of regulatory T cells

Abstract

Regulatory T cells (Tregs) are essential to maintain self-tolerance and immune homeostasis but, as components of the tumor microenvironment (TME), are also a major barrier to effective cancer immunosurveillance and immunotherapy. FH535 and its derivative Y3 are two N-aryl-benzene-sulfonamides (NABs) that inhibit HCC cell proliferation and tumor progression. However, the impact of NABs on the immune cells in the TME is not yet known. Analyses of explanted livers from patients with hepatocellular carcinoma (HCC) showed that high levels of tumor-infiltrating Tregs were associated with poor tumor differentiation. These results lead us to investigate the immunomodulatory effects of NABs in regulatory and effector T cells. Exposure of primary human Tregs to NABs induced a rapid but temporary increase of cell expansion, a gradual disruption of suppressor activity, and concomitant bioenergetics and autophagic flux dysregulations. In contrast to Tregs, no gross effects were observed in effector T cells. Addition of Rapamycin prevented the functional decay of Tregs and restored their metabolic profile, suggesting that NAB effects require the integrity of the mTOR pathway. This study revealed the immunomodulatory properties of NABs with a preferential impact on Treg activity and provided novel insights into the anti-tumor potential of sulfonamides.

RNA splicing regulator EIF3D regulates the tumor microenvironment through immunogene-related alternative splicing in head and neck squamous cell carcinoma

“…Prior investigations have established a positive relationship between increased CD8+ T cell infiltration within head and neck tumor tissue and improved survival rates [ 37 ], a trend also observed in other malignancies such as pancreatic cancer [ 38 ] and breast cancer [ 39 ]. Tregs play a pivotal role in preserving self-tolerance and immune equilibrium [ 40 ].…”

Metabolic Disruption Induced by mTOR Signaling Pathway Inhibition in Regulatory T-Cell Expansion for Clinical Application

“…CD25 + Treg cells were isolated from the leukapheresis product of end stage renal patients as previously described [ 16 , 17 , 18 ]. Briefly, the leukapheresis product was conjugated for 10 min at 4 °C with the CliniMACS CD25 MicroBeads reagent (Miltenyi Biotec).…”

“…Efforts to optimize the manufacturing process of clinical grade Treg cells are currently focused on improving the purity of the initial Treg cell population, reducing the expansion times to minimize contamination risks and processing costs, and increasing the potency of the final product. Recent studies reveal the impact of fine-tuning the mechanistic target of rapamycin (mTOR) activity to drive proper T cell function and fate decisions [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. The different sensitivities of effector and regulatory T cells to mTOR signaling modulation [ 7 ] supports the key role of this pathway in the distinct regulation of both cell type responses [ 8 ].…”

“…Our laboratory and others have addressed the integration of metabolic cues by the mTOR signaling as a critical determinant of Treg cell function and fate [ 16 , 17 , 18 , 19 , 20 ]. Our findings corroborated the distinct mitochondrial oxidation and glycolytic rates of Treg cells and effector Tconv, revealed the importance of the metabolic balance to preserve the functional integrity of Treg cells, and demonstrated the sensitivity of this tightly regulated balance to allosteric mTOR inhibitors.…”

High SERPINH1 expression predicts poor prognosis in lung adenocarcinoma

“…The tumor microenvironment can provide a specific environment and plays a non-negligible role in tumor development (28,29). The level of immune infiltration in the tumor microenvironment can promote or suppress the biological behavior of tumors (30)(31)(32)(33). Previous studies have shown that SERPINH1 is associated with tumor immune cell infiltration and may have an impact on tumor prognosis (13,27).…”