TY - JOUR
T1 - Anti-neoplastic sulfonamides alter the metabolic homeostasis and disrupt the suppressor activity of regulatory T cells
AU - Gedaly, Roberto
AU - Cornea, Virgilius
AU - Turcios, Lilia
AU - Edmisson, Jacob S.
AU - Harris, Dwight D.
AU - Watt, David S.
AU - Chapelin, Fanny
AU - Khurana, Aman
AU - Mei, Xiaonan
AU - Liu, Chunming
AU - Taylor, Isaac
AU - Gonzalez-Valdivieso, Juan
AU - Mitchel, Hunter
AU - Ruffing, Alexis
AU - Chishti, Asir
AU - Orozco, Gabriel
AU - Zwischenberger, Joseph
AU - Evers, B. Mark
AU - Marti, Francesc
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41598-022-23601-2
DO - 10.1038/s41598-022-23601-2
M3 - Article
C2 - 36352020
AN - SCOPUS:85141459940
SN - 2045-2322
VL - 12
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 19112
ER -