H <sub>2</sub> S-Prdx4 axis mitigates Golgi stress to bolster tumor-reactive T cell immunotherapeutic response
The role of tumor microenvironment (TME)-associated inadequate protein modification and trafficking due to insufficiency in Golgi function, leading to Golgi stress, in the regulation of T cell function is largely unknown. Here, we show that disruption of Golgi architecture under TME stress, identified by the decreased expression of GM130, was reverted upon treatment with hydrogen sulfide (H<sub>2</sub>S) donor GYY4137 or overexpressing cystathionine β-synthase (CBS), an enzyme involved in the biosynthesis of endogenous H<sub>2</sub>S, which also promoted stemness, antioxidant capacity, and increased protein translation, mediated in part by endoplasmic reticulum-Golgi shuttling of Peroxiredoxin-4. In in vivo models of melanoma and lymphoma, antitumor T cells conditioned ex vivo with exogenous H<sub>2</sub>S or overexpressing CBS demonstrated superior tumor control upon adoptive transfer. Further, T cells with high Golgi content exhibited unique metabolic and glycation signatures with enhanced antitumor capacity. These data suggest that strategies to mitigate Golgi network stress or using Golgi<sup>hi</sup> tumor-reactive T cells can improve tumor control upon adoptive transfer.
Authors
- Elizabeth G. Hill (ORCID: https://orcid.org/0000-0003-0896-4106)
- Susana Comte‐Walters
- Besim Öğretmen (ORCID: https://orcid.org/0000-0002-1019-5660)
- Silvia G. Vaena
- Stephanie Mills (ORCID: https://orcid.org/0000-0002-1478-8033)
- Anand S. Mehta (ORCID: https://orcid.org/0000-0002-9846-9389)
- Rasesh Y. Parikh (ORCID: https://orcid.org/0000-0002-6298-870X)
- Lauren E. Ball (ORCID: https://orcid.org/0000-0001-6780-1679)
- Vamsi K. Gangaraju (ORCID: https://orcid.org/0000-0003-3498-6624)
- Mónika Göőz
- Shikhar Mehrotra (ORCID: https://orcid.org/0000-0002-5411-9504)
- Stefano Berto (ORCID: https://orcid.org/0000-0001-9028-9458)
- Paramita Chakraborty (ORCID: https://orcid.org/0000-0002-0320-8697)
- Nathaniel Oberholtzer (ORCID: https://orcid.org/0000-0002-9080-5130)
- James W. Dressman (ORCID: https://orcid.org/0000-0002-6659-6367)
- Sang Ho Choi (ORCID: https://orcid.org/0000-0003-3865-1039)
- Eduardo N. Maldonado (ORCID: https://orcid.org/0000-0002-5285-3027)
- Gina Scurti
- Michael I. Nishimura (ORCID: https://orcid.org/0009-0008-2288-6021)
- Mohamed Faisal Kassir (ORCID: https://orcid.org/0000-0003-3501-1802)
- Martin J. Romeo (ORCID: https://orcid.org/0000-0001-7941-1862)
- Zacharia Hedley
- Satyajit Das (ORCID: https://orcid.org/0000-0002-9427-2132)
- Reid DeMass (ORCID: https://orcid.org/0000-0002-8859-600X)
Institutions
- Medical University of South Carolina (US)
- Loyola University Chicago (US)
- MUSC Hollings Cancer Center (US)
Publication Details
- Journal
- Science Advances
- Published
- 2024-11-15
- DOI
- https://doi.org/10.1126/sciadv.adp1152
- Citations
- 18
- Primary Topic
- Sulfur Compounds in Biology
- Type
- article
- Field-Weighted Citation Impact
- 5.31
Funders
- Silicon Valley Community Foundation
- Northwestern University
- Hollings Cancer Center, Medical University of South Carolina