c-Rel is a myeloid checkpoint for cancer immunotherapy

Li, Ting; Li, Xinyuan; Zamani, Ali; Wang, Wei; Lee, Chin-Nien; Li, Mingyue; Luo, George; Eiler, Emily; Sun, Honghong; Ghosh, Sankar; Jin, Jian; Murali, Ramachandran; Ruan, Qingguo; Shi, Weiyun; Chen, Youhai H.

doi:10.1038/s43018-020-0061-3

Cited by 76 publications

(103 citation statements)

References 49 publications

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“…Three different estimated activity patterns were obtained according to disease severity. First, we found TF activities that were down-regulated in CD1c + DC from moderate and severe patients including REL, recently shown to be a myeloid checkpoint 28 , FOS and JUN. Second, we found TF activities down-regulated in severe patients as compared to HC and moderate patients, including STAT2, 3 and 6, involved in immune responses by controlling transcription of cytokine-induced genes.…”

Section: Downregulation Of Mhc-ii and Loss Of Ciita Activity In Cd1c mentioning

confidence: 83%

Single cell RNA sequencing of blood antigen-presenting cells in severe Covid-19 reveals multi-process defects in antiviral immunity

Saichi

Ladjemi

Korniotis

et al. 2020

Preprint

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COVID-19 can lead to life-threatening acute respiratory failure, characterized by simultaneous increase in inflammatory mediators and viral load. The underlying cellular and molecular mechanisms remain unclear. We performed single-cell RNA-sequencing to establish an exhaustive high-resolution map of blood antigen-presenting cells (APC) in 7 COVID-19 patients with moderate or severe pneumonia, at day-1 and day-4 post-admission, and two healthy donors. We generated a unique dataset of 31,513 high quality APC, including monocytes and rare dendritic cell (DC) subsets. We uncovered multiprocess and previously unrecognized defects in anti-viral immune defense in specific APC compartments from severe patients: i) increase of pro-apoptotic genes exclusively in pDC, which are key effectors of antiviral immunity, ii) sharp decrease of innate sensing receptors, TLR7 and DHX9, in pDC and cDC1, respectively, iii) down-regulation of antiviral effector molecules, including Interferon stimulated genes (ISG) in all monocyte subsets, and iv) decrease of MHC class II-related genes, and MHC class II transactivator (CIITA) activity in cDC2, suggesting a viral inhibition of antigen presentation. These novel mechanisms may explain patient aggravation and suggest strategies to restore defective immune defense.

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Section: Downregulation Of Mhc-ii and Loss Of Ciita Activity In Cd1c mentioning

confidence: 83%

Single cell RNA sequencing of blood antigen-presenting cells in severe Covid-19 reveals multi-process defects in antiviral immunity

Saichi

Ladjemi

Korniotis

et al. 2020

Preprint

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“…Cytokines, induced by LAP, travel to the myeloid compartment where they promote expansion of MDSC precursors and direct their differentiation into suppressor cells. Within MDSCs, activated C/EBPß directly binds to and promotes the transcription of immunosuppressive enzymes including Arg1, Nos2, Nox2, and Cox2 ( 27 , 36 , 57 ). These enzymes are crucial members of the MDSC immunosuppressive machinery.…”

Section: C/ebp Protein Familymentioning

confidence: 99%

“…Although previously thought to primarily function in the lymphoid compartment, mounting evidence suggests a significant role for c-Rel in myeloid cells. We recently showed that c-Rel regulates MDSC expansion and function in cancer ( 57 ). Both global and myeloid-specific c-Rel deletion blocked tumor growth and markedly decreased MDSC accumulation in melanoma and lymphoma mice models.…”

Section: C-rel a New Regulator Of Mdsc Differentiation And Functionmentioning

confidence: 99%

Myeloid-Derived Suppressor Cell Differentiation in Cancer: Transcriptional Regulators and Enhanceosome-Mediated Mechanisms

Fultang

et al. 2021

Front. Immunol.

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Myeloid-derived Suppressor Cells (MDSCs) are a sub-population of leukocytes that are important for carcinogenesis and cancer immunotherapy. During carcinogenesis or severe infections, inflammatory mediators induce MDSCs via aberrant differentiation of myeloid precursors. Although several transcription factors, including C/EBPβ, STAT3, c-Rel, STAT5, and IRF8, have been reported to regulate MDSC differentiation, none of them are specifically expressed in MDSCs. How these lineage-non-specific transcription factors specify MDSC differentiation in a lineage-specific manner is unclear. The recent discovery of the c-Rel−C/EBPβ enhanceosome in MDSCs may help explain these context-dependent roles. In this review, we examine several transcriptional regulators of MDSC differentiation, and discuss the concept of non-modular regulation of MDSC signature gene expression by transcription factors such as c-Rel and C/EBPß.

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“…Another well-known, though poorly selective, IKK inhibitor, curcumin, decreases the number of intra-tumoral Treg cells in preclinical models of cancer [92][93][94], and enhances Th1 cells, while decreasing Treg cells in patients with lung and colon cancer [95,96]. Finally, c-Rel inhibition using the methylxanthine derivative Pentoxifylline (PTXF) or the selective c-Rel inhibitors, IT-603 or R96A, significantly reduces tumor growth and synergizes with anti-PD-1/Programed cell Death Ligand 1 (PD-L1) therapy as well as doxorubicin [26,[97][98][99]. Interestingly, it seems that most of these drugs, in particular mepazine and PTXF, act through the destabilization of tumor-infiltrating Treg cells by inducing their expression of effector cytokines, rather than by depleting the cells or directly perturbing their inhibitory program.…”

Section: The Many Roles Of Nf-κb In Treg Cellsmentioning

confidence: 99%

“…No severe adverse effects of the c-Rel inhibitor PTXF (commercialized as Trental) were reported when administered to humans [106]. The recent description of potent and apparently safe c-Rel inhibitors further advocates for such a use [97,99].…”

Section: Nf-κb Is a Nexus Regulator Of The Treg Cell Transcriptional mentioning

confidence: 99%

Transcriptional Control of Regulatory T Cells in Cancer: Toward Therapeutic Targeting?

Stéphan¹,

Lautraite²,

Voisin³

et al. 2020

Cancers

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Extensive research in the past decades has highlighted the tight link between immunity and cancer, leading to the development of immunotherapies that have revolutionized cancer care. However, only a fraction of patients display durable responses to these treatments, and a deeper understanding of the cellular and mechanisms orchestrating immune responses to tumors is mandatory for the discovery of novel therapeutic targets. Among the most scrutinized immune cells, Forkhead Box Protein P3 (Foxp3)+ Regulatory T cells (Treg cells) are central inhibitors of protective anti-tumor immunity. These tumor-promoting functions render Treg cells attractive immunotherapy targets, and multiple strategies are being developed to inhibit their recruitment, survival, and function in the tumor microenvironment. In this context, it is critical to decipher the complex and multi-layered molecular mechanisms that shape and stabilize the Treg cell transcriptome. Here, we provide a global view of the transcription factors, and their upstream signaling pathways, involved in the programming of Treg cell homeostasis and functions in cancer. We also evaluate the feasibility and safety of novel therapeutic approaches aiming at targeting specific transcriptional regulators.

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c-Rel is a myeloid checkpoint for cancer immunotherapy

Cited by 76 publications

References 49 publications

Single cell RNA sequencing of blood antigen-presenting cells in severe Covid-19 reveals multi-process defects in antiviral immunity

Single cell RNA sequencing of blood antigen-presenting cells in severe Covid-19 reveals multi-process defects in antiviral immunity

Myeloid-Derived Suppressor Cell Differentiation in Cancer: Transcriptional Regulators and Enhanceosome-Mediated Mechanisms

Transcriptional Control of Regulatory T Cells in Cancer: Toward Therapeutic Targeting?

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