Immune regulation and cytotoxic T cell activation of IL-10 agonists – Preclinical and clinical experience

Oft, Martin

doi:10.1016/j.smim.2019.101325

Cited by 42 publications

(37 citation statements)

References 106 publications

(151 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, many studies in this field demonstrated that its role in cancer is more complex than initially envisioned [ 243 , 244 , 245 , 246 ]. Intriguingly, IL-10-based therapy, including pegylated IL-10 (Pegilodecakin), is much more efficient than therapies neutralizing IL-10 effects [ 246 , 247 , 248 ].…”

Section: Modulation Of Epcs To Inhibit Their Tumor-promoting Effecmentioning

confidence: 99%

Tumor Immune Evasion Induced by Dysregulation of Erythroid Progenitor Cells Development

Grzywa

Justyniarska

Nowis

et al. 2021

Cancers

View full text Add to dashboard Cite

Cancer cells harness normal cells to facilitate tumor growth and metastasis. Within this complex network of interactions, the establishment and maintenance of immune evasion mechanisms are crucial for cancer progression. The escape from the immune surveillance results from multiple independent mechanisms. Recent studies revealed that besides well-described myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) or regulatory T-cells (Tregs), erythroid progenitor cells (EPCs) play an important role in the regulation of immune response and tumor progression. EPCs are immature erythroid cells that differentiate into oxygen-transporting red blood cells. They expand in the extramedullary sites, including the spleen, as well as infiltrate tumors. EPCs in cancer produce reactive oxygen species (ROS), transforming growth factor β (TGF-β), interleukin-10 (IL-10) and express programmed death-ligand 1 (PD-L1) and potently suppress T-cells. Thus, EPCs regulate antitumor, antiviral, and antimicrobial immunity, leading to immune suppression. Moreover, EPCs promote tumor growth by the secretion of growth factors, including artemin. The expansion of EPCs in cancer is an effect of the dysregulation of erythropoiesis, leading to the differentiation arrest and enrichment of early-stage EPCs. Therefore, anemia treatment, targeting ineffective erythropoiesis, and the promotion of EPC differentiation are promising strategies to reduce cancer-induced immunosuppression and the tumor-promoting effects of EPCs.

show abstract

Section: Modulation Of Epcs To Inhibit Their Tumor-promoting Effecmentioning

confidence: 99%

Tumor Immune Evasion Induced by Dysregulation of Erythroid Progenitor Cells Development

Grzywa

Justyniarska

Nowis

et al. 2021

Cancers

View full text Add to dashboard Cite

show abstract

“…In addition to its anti-inflammatory activities, IL-10 can increase the cytotoxic function of CD8 + T cells, augmenting their ability to target tumours and boosting the anti-cancer response (15). This property seems paradoxical because IL-10 in the tumour microenvironment is linked to tumour evasion of the immune response, most likely due to IL-10's inhibitory effects on antigen presentation (16,17).…”

Section: Introductionmentioning

confidence: 99%

Engineered IL-10 variants elicit potent immunomodulatory effects at low ligand doses

et al. 2020

View full text Add to dashboard Cite

Interleukin-10 (IL-10) is a dimeric cytokine with both immunosuppressive and immunostimulatory activities; however, IL-10–based therapies have shown only marginal clinical benefits. Here, we explored whether the stability of the IL-10 receptor complex contributes to the immunomodulatory potency of IL-10. We generated an IL-10 mutant with enhanced affinity for its IL-10Rβ receptor using yeast surface display. Compared to the wild-type cytokine, the affinity-enhanced IL-10 variants recruited IL-10Rβ more efficiently into active cell surface signaling complexes and triggered greater STAT1 and STAT3 activation in human monocytes and CD8+ T cells. These effects, in turn, led to more robust induction of IL-10–mediated gene expression programs at low ligand concentrations in both human cell subsets. IL-10–regulated genes are involved in monocyte energy homeostasis, migration, and trafficking and in CD8+ T cell exhaustion. At nonsaturating doses, IL-10 did not induce key components of its gene expression program, which may explain its lack of efficacy in clinical settings. Our engineered IL-10 variant showed a more robust bioactivity profile than that of wild-type IL-10 at low doses in monocytes and CD8+ T cells. Moreover, CAR-modified T cells expanded with the engineered IL-10 variant displayed superior cytolytic activity than those expanded with wild-type IL-10. Our study provides insights into how IL-10 receptor complex stability fine-tunes IL-10 biology and opens new opportunities to revitalize failed IL-10 therapies.

show abstract

“…Here we found that mice infected by WSN induced higher levels of IFNα, IFNγ, IL-2, IL-4, and IL-6 known to activate the antibody response, while the NA-defective WSN induced higher levels of IL-10, IL-12, and IL-27 known to trigger the cellular immune response ( Fig. 4a-h) [13][14][15][16][17][18] . In a recent study, IL-17D was shown to be a critical cytokine during IAV infection to suppress the activity of CD8 + T cells through regulation of dendritic cells 19 .…”

Section: Resultsmentioning

confidence: 63%

Influenza virus neuraminidase regulates host CD8+ T-cell response in mice

Chuang

Wong

2020

Commun Biol

View full text Add to dashboard Cite

Influenza A virus (IAV)-specific CD8+ T-cell response was shown to provide protection against pandemic and seasonal influenza infections. However, the response was often relatively weak and the mechanism was unclear. Here, we show that the composition of IAV released from infected cells is regulated by the neuraminidase (NA) activity and the cells infected by NA-defective virus cause intracellular viral protein accumulation and cell death. In addition, after uptake of NA-defective viruses by dendritic cells (DCs), an expression of the major histocompatibility complex class I is induced to activate IAV-specific CD8+ T-cell response. When mice were infected by NA-defective IAV, a CD8+ T-cell response to the highly conserved viral antigens including PB1, NP, HA, M1, M2 and NS1 was observed along with the increasing expression of IL10, IL12 and IL27. Vaccination of mice with NA-defective H1N1 A/WSN/33 induced a strong IAV-specific CD8+ T cell response against H1N1, H3N2 and H5N1. This study reveals the role of NA in the IAV-specific CD8+ T-cell response and virion assembly process, and provides an alternative direction toward the development of universal influenza vaccines.

show abstract

Immune regulation and cytotoxic T cell activation of IL-10 agonists – Preclinical and clinical experience

Cited by 42 publications

References 106 publications

Tumor Immune Evasion Induced by Dysregulation of Erythroid Progenitor Cells Development

Tumor Immune Evasion Induced by Dysregulation of Erythroid Progenitor Cells Development

Engineered IL-10 variants elicit potent immunomodulatory effects at low ligand doses

Influenza virus neuraminidase regulates host CD8+ T-cell response in mice

Contact Info

Product

Resources

About