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

Roberto Gedaly, Virgilius Cornea, Lilia Turcios, Jacob S. Edmisson, Dwight D. Harris, David S. Watt, Fanny Chapelin, Aman Khurana, Xiaonan Mei, Chunming Liu, Isaac Taylor, Juan Gonzalez-Valdivieso, Hunter Mitchel, Alexis Ruffing, Asir Chishti, Gabriel Orozco, Joseph Zwischenberger, B. Mark Evers, Francesc Marti

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1 Scopus citations


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.

Original languageEnglish
Article number19112
JournalScientific Reports
Issue number1
StatePublished - Dec 2022

Bibliographical note

Funding Information:
This research was supported by the University of Kentucky Alliance Research Initiative (TILT Alliance) and by the National Center for Advancing Translational Sciences, NIH Grant UL1TR001998, to R.G. and F.M. The Biospecimen Procurement and Translational Pathology (BPTP), the Redox Metabolism (RMSR) and the Flow Cytometry and Immune Monitoring (FCIM) shared resource facilities received support from the National Cancer Institute, NIH Cancer Center Support Grant P30CA177558. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Publisher Copyright:
© 2022, The Author(s).

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