Suppressors of cytokine signaling: Potential immune checkpoint molecules for cancer immunotherapy

Chikuma, Shunsuke; Kanamori, Mitsuhiro; Mise-Omata, Setsuko; Yoshimura, Akihiko

doi:10.1111/cas.13194

Cited by 91 publications

(67 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SOCS1 protein inhibits the signaling through the pathway stimulated by various cytokines including type I (e.g. IFN-α, IFN-β) and type II (IFN-γ) interferons [53]. Hence, SOCS1 appears to be another gene of innate immunity system regulated by p53.…”

Section: Discussionmentioning

confidence: 99%

Synergistic activation of p53 by actinomycin D and nutlin-3a is associated with the upregulation of crucial regulators and effectors of innate immunity

Krześniak

Zajkowicz

Gdowicz-Kłosok

et al. 2020

Cellular Signalling

View full text Add to dashboard Cite

A B S T R A C TActinomycin D and nutlin-3a (A + N) activate p53, partly through induction of phosphorylation on Ser392. The death of A549 cells induced by A + N morphologically resembles inflammation-inducing pyroptosis -cell destruction triggered by activated caspase-1. The treatment with A + N (or camptothecin) strongly upregulated caspase-1 and its two activators: IFI16 and NLRP1, however, caspase-1 activation was not detected. A549 cells may have been primed for pyroptosis, with the absence of a crucial trigger. The investigation of additional innate immunity elements revealed that A + N (or camptothecin) stimulated the expression of NLRX1, STING (stimulator of interferon genes) and two antiviral proteins, IFIT1 and IFIT3. IFI16 and caspase-1 are coded by p53regulated genes which led us to investigate regulation of NLRP1, NLRX1, STING, IFIT1 and IFIT3 in p53-dependent mode. The upregulation of NLRP1, NLRX1 and STING was attenuated in p53 knockdown cells. The upsurge of the examined genes, and activation of p53, was inhibited by C16, an inhibitor of PKR kinase. PKR was tested due to its ability to phosphorylate p53 on Ser392. Surprisingly, C16 was active even in PKR knockdown cells. The ability of C16 to prevent activation of p53 and expression of innate immunity genes may be the source of its strong anti-inflammatory action. Moreover, cells exposed to A + N can influence neighboring cells in paracrine fashion, for instance, they shed ectodomain of COL17A1 protein and induce, in p53-dependent mode, the expression of gene for interleukin-7. Further, the activation of p53 also spurred the expression of SOCS1, an inhibitor of interferon triggered STAT1-dependent signaling. We conclude that, stimulation of p53 primes cells for the production of interferons (through upregulation of STING), and may activate negative-feedback within this signaling system by enhancing the production of SOCS1.

show abstract

Section: Discussionmentioning

confidence: 99%

Synergistic activation of p53 by actinomycin D and nutlin-3a is associated with the upregulation of crucial regulators and effectors of innate immunity

Krześniak

Zajkowicz

Gdowicz-Kłosok

et al. 2020

Cellular Signalling

View full text Add to dashboard Cite

show abstract

“…310 As an active transcription factor, the STAT dimer directly affects the expression of related genes and then changes the proliferation or differentiation of target cells. 311 Constitutive activation of JAKs and STATs was first recognized as being associated with malignancy in the 1990s. 312 Based on current studies, JAK2 mutation and abnormal activation of STAT3 are prone to occur in many tumors.…”

Section: Major Signaling Pathways In Cscsmentioning

confidence: 99%

Targeting cancer stem cell pathways for cancer therapy

Yang

Shi

Zhao

et al. 2020

Sig Transduct Target Ther

1,225

998

View full text Add to dashboard Cite

Since cancer stem cells (CSCs) were first identified in leukemia in 1994, they have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. The biological activities of CSCs are regulated by several pluripotent transcription factors, such as OCT4, Sox2, Nanog, KLF4, and MYC. In addition, many intracellular signaling pathways, such as Wnt, NF-κB (nuclear factor-κB), Notch, Hedgehog, JAK-STAT (Janus kinase/signal transducers and activators of transcription), PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT/mammalian target of rapamycin), TGF (transforming growth factor)/SMAD, and PPAR (peroxisome proliferator-activated receptor), as well as extracellular factors, such as vascular niches, hypoxia, tumor-associated macrophages, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, extracellular matrix, and exosomes, have been shown to be very important regulators of CSCs. Molecules, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) cells have been developed to specifically target CSCs, and some of these factors are already undergoing clinical trials. This review summarizes the characterization and identification of CSCs, depicts major factors and pathways that regulate CSC development, and discusses potential targeted therapy for CSCs.Signal Transduction and Targeted Therapy (2020) 5:8; https://doi.

show abstract

“…It is well‐known that inhibitory receptors such as programmed death 1 (PD‐1) and cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4) can inhibit the function of tumor‐specific T cells by interacting with their ligands in the tumor microenvironment . Accordingly, PD‐1‐and CTLA‐4‐targeted therapies are effective for the treatment of tumors through the restoration of the immune response of exhausted T cells . The main focus of immunotherapy research has been determining how to reduce exhaustion and to maintain the ability for memory formation of tumor‐specific CD8 + T cells.…”

Section: Introductionmentioning

confidence: 99%

“…8 Accordingly, PD-1-and CTLA-4-targeted therapies are effective for the treatment of tumors through the restoration of the immune response of exhausted T cells. 9 The main focus of immunotherapy research has been determining how to reduce exhaustion and to maintain the ability for memory formation of tumor-specific CD8 + T cells.…”

Section: Introductionmentioning

confidence: 99%

Reinforce the antitumor activity of CD8⁺ T cells via glutamine restriction

et al. 2018

View full text Add to dashboard Cite

The antitumor activity of activated CD8+ T cells in the tumor microenvironment seems to be limited due to their being metabolically unfit. This metabolic unfitness is closely associated with T‐cell exhaustion and impairment of memory formation, which are barriers to successful antitumor adoptive immunotherapy. We therefore assessed the role of glutamine metabolism in the antitumor activity of CD8+ T cells using a tumor‐inoculated mouse model. The adoptive transfer of tumor‐specific CD8+ T cells cultured under glutamine‐restricted (dGln) conditions or CD8+ T cells treated with specific inhibitors of glutamine metabolism efficiently eliminated tumors and led to better survival of tumor‐inoculated mice than with cells cultured under control (Ctrl) conditions. The decreased expression of PD‐1 and increased Ki67 positivity among tumor‐infiltrating CD8+ T cells cultured under dGln conditions suggested that the inhibition of glutamine metabolism prevents CD8+ T‐cell exhaustion in vivo. Furthermore, the transferred CD8+ T cells cultured under dGln conditions expanded more efficiently against secondary OVA stimulation than did CD8+ T cells under Ctrl conditions. We found that the expression of a pro‐survival factor and memory T cell‐related transcription factors was significantly higher in CD8+ T cells cultured under dGln conditions than in those cultured under Ctrl conditions. Given these findings, our study uncovered an important role of glutamine metabolism in the antitumor activity of CD8+ T cells. The novel adoptive transfer of tumor‐specific CD8+ T cells cultured in glutamine‐restricted conditions may be a promising approach to improve the efficacy of cell‐based adoptive immunotherapy.

show abstract

Suppressors of cytokine signaling: Potential immune checkpoint molecules for cancer immunotherapy

Cited by 91 publications

References 63 publications

Synergistic activation of p53 by actinomycin D and nutlin-3a is associated with the upregulation of crucial regulators and effectors of innate immunity

Synergistic activation of p53 by actinomycin D and nutlin-3a is associated with the upregulation of crucial regulators and effectors of innate immunity

Targeting cancer stem cell pathways for cancer therapy

Reinforce the antitumor activity of CD8⁺ T cells via glutamine restriction

Contact Info

Product

Resources

About

Suppressors of cytokine signaling: Potential immune checkpoint molecules for cancer immunotherapy

Cited by 91 publications

References 63 publications

Synergistic activation of p53 by actinomycin D and nutlin-3a is associated with the upregulation of crucial regulators and effectors of innate immunity

Synergistic activation of p53 by actinomycin D and nutlin-3a is associated with the upregulation of crucial regulators and effectors of innate immunity

Targeting cancer stem cell pathways for cancer therapy

Reinforce the antitumor activity of CD8+ T cells via glutamine restriction

Contact Info

Product

Resources

About

Reinforce the antitumor activity of CD8⁺ T cells via glutamine restriction