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Cited by 24Sulfur Compounds in BiologyRedox biology and oxidative stressCancer Immunotherapy and Biomarkers

H 2 S-Prdx4 axis mitigates Golgi stress to bolster tumor-reactive T cell immunotherapeutic response

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Oberholtzer, Nathaniel, Chakraborty, Paramita, Kassir, Mohamed Faisal, Dressman, James, Das, Satyajit, Mills, Stephanie, Comte-Walters, Susana, Gooz, Monika +16 more·2024·Science Advances
DOI 10.1126/sciadv.adp1152PMC PMC11566994
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Abstract

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 2 S) donor GYY4137 or overexpressing cystathionine β-synthase (CBS), an enzyme involved in the biosynthesis of endogenous H 2 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 2 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 hi tumor-reactive T cells can improve tumor control upon adoptive transfer.

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Authors
Oberholtzer, N., Chakraborty, P., Kassir, M. F., Dressman, J., Das, S., Mills, S., Comte-Walters, S., Gooz, M., Choi, S., Parikh, R. Y., Hedley, Z., Vaena, S., DeMass, R., Scurti, G., Romeo, M., Gangaraju, V. K., Berto, S., Hill, E., Ball, L. E., Mehta, A. S., Maldonado, E. N., Nishimura, M. I., Ogretmen, B., & Mehrotra, S.
Affiliations
  • Medical University of South Carolina (US)
  • Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, USA.
  • Loyola University Chicago (US)
  • Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
Corresponding author
Mehrotra, Shikhar
ORCID
Venue
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Published
2024-11-15
Volume
10
Issue
46
Pages
eadp1152-eadp1152
ISSN
2375-2548 (ISSN-L)
DOI
10.1126/sciadv.adp1152
PMC
PMC11566994
OpenAlex
W4404400042
Cited by
24
References
2
Citations by year
2026: 12 · 2025: 12
FWCI
3.85
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Science Advances (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Silicon Valley Community Foundation
  • Northwestern University
  • National Institutes of Health (1s10od018113-01a1, 1s10od025126-01)
  • Hollings Cancer Center, Medical University of South Carolina
  • National Cancer Institute (R42CA239952, R01CA236379, R41CA271958, R01CA250458, P30CA138313, R01CA214461)
  • National Institute of General Medical Sciences (R01GM130846, P30GM140964)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK123704)
  • National Institute of Dental and Craniofacial Research (R01DE016572)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
hydrogen sulfide, peroxiredoxin 4, Golgi stress, cystathionine beta-synthase, tumor microenvironment, adoptive T cell therapy, melanoma, lymphoma, GM130, protein glycation, T cell metabolism, antitumor immunity
MeSH terms
Animals, Cystathionine beta-Synthase, Golgi Apparatus, Humans, Hydrogen Sulfide, Immunotherapy, Stress, Physiological, T-Lymphocytes, Cell Line, Tumor, Mice, Tumor Microenvironment

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