Targeting the NF-κB pathway as a potential regulator of immune checkpoints in cancer immunotherapy

Ebrahimi, Nasim; Abdulwahid, Al-Hasnawi Rasool Riyadh; Mansouri, Atena; Karimi, Nasrin; Bostani, Rashid Jafardoust; Beiranvand, Sheida; Adelian, Samaneh; Khorram, Roya; Vafadar, Reza; Hamblin, Michael R.; Aref, Amir Reza

doi:10.1007/s00018-023-05098-8

Cited by 9 publications

(1 citation statement)

References 239 publications

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“…NFkB is shown to maintain the tumor promoting phenotype of TAM in certain cancers 29 . NFkB has been also linked to evolution of inflammatory tumors 30 . In our study, we found that in TAMs, the NFkB was highly upregulated and after TD treatment, NFkB downregulated significantly ( Figure 4c ).…”

Section: Resultsmentioning

confidence: 99%

Designer DNA nanocages modulate anti-oxidative and anti-inflammatory responses in tumor associated macrophages

Vaswani,

Bhatia

2024

Preprint

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Cancer is a complex disease, with multiple treatment modalities, but no definitive cure. The tumor microenvironment contributes to the complexity of the disease by forming a niche of multiple cell types supporting each other to carry out various cellular functions. Tumor associated macrophages are one such kind of cells which support the tumor microenvironment via immunosuppression. DNA tetrahedron (TD), a widely explored DNA nanocage, has shown a lot of potential in therapeutics. However, the role of TD still remains quite unexplored in immunology. Here, we first establish the anti-oxidative and anti-inflammatory role of TD. We then proceed with using TD as a therapeutic agent in tumor associated macrophages by modulating the response of PD-L1. The findings of this work create a base for TD in biological applications such as cancer immunotherapy.Graphical AbstractImmunomodulatory effects of DNA nanocages on tumour associated macrophages

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Section: Resultsmentioning

confidence: 99%

Designer DNA nanocages modulate anti-oxidative and anti-inflammatory responses in tumor associated macrophages

Vaswani,

Bhatia

2024

Preprint

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LPA suppresses HLA-DR expression in human melanoma cells: a potential immune escape mechanism involving LPAR1 and DR6-mediated release of IL-10

Major,

Lin,

Lee

et al. 2024

Acta Pharmacol Sin

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While immune checkpoint inhibitors (ICIs) are promising in the treatment of metastatic melanoma, about half of patients do not respond well to them. Low levels of human leukocyte antigen-DR (HLA-DR) in tumors have been shown to negatively influence prognosis and response to ICIs. Lysophosphatidic acid (LPA) is produced in large amounts by melanoma and is abundantly present in the tumor microenvironment. LPA induces the release of various cytokines and chemokines from tumor cells, which affect cancer development, metastasis, and tumor immunity. In the present study, we investigated the role of LPA-induced IL-10 release in regulating HLA-DR expression and the underlying mechanisms in human melanoma cells. We showed that LPA (0.001–10 μM) dose-dependently increased DR6 transcript levels through activating LPAR1 in HEK293T cells. Knockdown of NF-κB1 abrogated the LPA-increased DR6 expression without affecting basal DR6 expression in both A2058 and A375 melanoma cell lines. LPA (10 µM) significantly increased IL-10 transcripts in A2058 and A375 melanoma cells, the effect was abolished by pharmacological inhibition of LPAR1 or knockdown of DR6. We found a statistically significant correlation between the expression of LPAR1, DR6 and IL-10 in human melanoma tissue and an association between increased expression of LPAR1 and reduced effectiveness of ICI therapy. We demonstrated that LPA (10 µM) markedly suppressed HLA-DR expression in both A375 and A2058 melanoma cells via activating the LPAR1-DR6-IL-10 pathway. These data suggest that the LPAR1-DR6-IL-10 autocrine loop could constitute a novel mechanism used by tumor cells to evade immunosurveillance by decreasing HLA-DR expression.

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Deletion of Nrf1 exacerbates oxidative stress-induced cellular senescence by disrupting the cell homeostasis

Lyu,

Wang,

Qiu

et al. 2024

Preprint

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Nuclear factor erythroid-derived 2-like 1(Nrf1,encoded by Nfe2l1), an essential transcription factor of the cap'n'collar basic-region leucine zipper(CNC-bZIP)family, is highly conserved with its homologous Nuclear factor erythroid-derived 2-like 2(Nrf2,encoded by Nfe2l2). Of note, Nrf1 possesses a remarkable anti-senescence potential, but it has not been comprehensively characterized to date. Conversely, Nrf1α-/- cells undergoing senescence display hallmarks of senescence, comprising heightened activity of senescence-associated β-galactosidase, decreased cell vitality, cell growth arrest, and increased expression of the senescence-associated secretory phenotype. Further investigation showed cellular senescence in Nrf1α-/- cells is not a consequence of Nrf2 accumulation. On the contrary, Nrf2 could alleviate, but not halt or reverse, senescence of Nrf1α-/- cells. This is predominantly attributable to the fact that, different from Nrf2, the deficiency of Nrf1 brings about activation of both p21 and RB pathwanys independently of p53, but disrupts STAG2- and SMC3-dependent chromosomal homeostasis so to drive cell senescence. Here, we discover the significant anti-senescence capacity of Nrf1 and highlight two mechanisms underlying the protective function of Nrf1, which stem from its response to stress and its role in maintaining cellular homeostasis.

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Targeting the NF-κB pathway as a potential regulator of immune checkpoints in cancer immunotherapy

Cited by 9 publications

References 239 publications

Designer DNA nanocages modulate anti-oxidative and anti-inflammatory responses in tumor associated macrophages

Designer DNA nanocages modulate anti-oxidative and anti-inflammatory responses in tumor associated macrophages

LPA suppresses HLA-DR expression in human melanoma cells: a potential immune escape mechanism involving LPAR1 and DR6-mediated release of IL-10

Deletion of Nrf1 exacerbates oxidative stress-induced cellular senescence by disrupting the cell homeostasis

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