Targeting of Nrf2 improves antitumoral responses by human NK cells, TIL and CAR T cells during oxidative stress
Open accessAbstract
Background: Adoptive cell therapy using cytotoxic lymphocytes is an efficient immunotherapy against solid and hematological cancers. However, elevated levels of reactive oxygen species (ROS) in the hostile tumor microenvironment can impair NK cell and T cell function. Auranofin, a gold (I)-containing phosphine compound, is a strong activator of the transcription factor Nrf2. Nrf2 controls a wide range of downstream targets important for the cells to obtain increased resistance to ROS. In this study, we present a strategy using auranofin to render human cytotoxic lymphocytes resistant toward oxidative stress. Methods: Melanoma patient-derived tumor infiltrating lymphocytes (TIL) and healthy donor-derived NK cells and CD19-directed CAR T cells were pretreated with a low dose of auranofin. Their resistance toward oxidative stress was assessed by measuring antitumoral responses (killing-assay, degranulation/CD107a, cytokine production) and intracellular ROS levels (flow cytometry) in conditions of oxidative stress. To confirm that the effects were Nrf2 dependent, the transcription level of Nrf2-driven target genes was analyzed by qPCR. Results: Pretreatment of human TIL and NK cells ex vivo with a low-dose auranofin significantly lowered their accumulation of intracellular ROS and preserved their antitumoral activity despite high H 2 O 2 levels or monocyte-derived ROS. Furthermore, auranofin pretreatment of CD19 CAR-T cells or TIL increased their elimination of CD19 +tumor cells or autologous tumor spheroids, respectively, especially during ROS exposure. Analysis of Nrf2-driven target genes revealed that the increased resistance against ROS was Nrf2 dependent. Conclusion: These novel findings suggest that Nrf2 activation in human cytotoxic lymphocytes could be used to enhance the efficacy of adoptive cell therapy.
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In an MC38 colon cancer model, methanol raised serum formate and improved αPD1 efficacy.
“methanol, which elevated serum formate levels, enhanced αPD1 efficacy in a MC38 colon cancer model93.”
From Exercise-induced microbiota metabolite enhances CD8 T cell antitumor immunity promoting immunotherapy efficacy (2025) · cites this paper as [93]
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“Antitumor activity of NK cells could be restored by activation of the nuclear factor E2-related factor 2 (NRF2) antioxidant pathway (30, 31).”
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- Authors
- Renken, S., Nakajima, T., Magalhaes, I., Mattsson, J., Lundqvist, A., Arnér, E. S. J., Kiessling, R., & Wickström, S. L.
- Affiliations
- Karolinska Institutet (SE)
- Karolinska University Hospital (SE)
- Princess Margaret Cancer Centre (CA)
- Corresponding author
- Wickström, Stina Linnea
- ORCID
- Venue
- Journal for ImmunoTherapy of Cancer
- Publisher
- BMJ
- Published
- 2022-06
- Volume
- 10
- Issue
- 6
- Pages
- e004458
- ISSN
- 2051-1426 (ISSN-L)
- PMC
- PMC9226989
- OpenAlex
- W4283319121
- Cited by
- 67
- References
- 55
- Citations by year
- 2026: 13 · 2025: 24 · 2024: 15 · 2023: 9 · 2022: 6
- FWCI
- 4.49
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Journal for ImmunoTherapy of Cancer (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Stiftelsen Tornspiran
- Cancerfonden (190104Pj01H, 21 1463 Pj, 2019-, 19 0002 FE, #CAN 2018/451), 190108Us01H, 19 0359 Pj 01 H9, 19 0359 Pj)
- Kommunfullmäktige, Stockholms Stad (2018-1157)
- Karolinska Institutet (2–5586/2017)
- Knut och Alice Wallenbergs Stiftelse (2019‐0059, KAW 2015.0063, KAW2015, KAW 2019.0059)
- Vetenskapsrådet (2019-01212, 2021-02214, 2018-)
- Cancerföreningen i Stockholm (201232)
- Radiumhemmets Forskningsfonder (181183)
- Medical Research Council
- National Research, Development and Innovation Office (ED_18-1-2019-0025, TKP-2021-EGA, TKP2021-EGA-44, TKP 2021)
- National Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Keywords
- Nrf2, auranofin, oxidative stress, reactive oxygen species, adoptive immunotherapy, natural killer cells, tumor-infiltrating lymphocytes, chimeric antigen receptor T cells, CD19, melanoma, cytotoxic lymphocytes, tumor microenvironment
- MeSH terms
- Auranofin, Cytotoxicity, Immunologic, Humans, Hydrogen Peroxide, Immunotherapy, Killer Cells, Natural, Melanoma, T-Lymphocytes, Lymphocytes, Tumor-Infiltrating, Reactive Oxygen Species, Oxidative Stress, Antigens, CD19, NF-E2-Related Factor 2, Tumor Microenvironment
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