<i>Cblb</i>-deficient T cells are less susceptible to PD-L1-mediated inhibition

Peer, Sebastian; Baier, Gottfried; Gruber, Thomas

doi:10.18632/oncotarget.18360

Cited by 20 publications

(23 citation statements)

References 61 publications

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“…Early studies demonstrated that Cbl-b can be re-expressed in response to CTLA-4 signaling, and CTLA-4 deficient T cells display reduced Cbl-b expression (153). Recent studies suggest that T cells deficient in Cbl-b are less susceptible to PD-1 inhibitory signaling in vitro (154, 155). These findings are consistent with a study suggesting that SHP-1, which plays an important role in downstream PD-1 and CTLA-4 signaling pathway, controls Cbl-b activity through direct phosphorylation (156).…”

Section: Reported Cases Of Treg Resistancementioning

confidence: 99%

Turning the Tide Against Regulatory T Cells

et al. 2019

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Regulatory T (Treg) cells play crucial roles in health and disease through their immunosuppressive properties against various immune cells. In this review we will focus on the inhibitory role of Treg cells in anti-tumor immunity. We outline how Treg cells restrict T cell function based on our understanding of T cell biology, and how we can shift the equilibrium against regulatory T cells. To date, numerous strategies have been proposed to limit the suppressive effects of Treg cells, including Treg cell neutralization, destabilizing Treg cells and rendering T cells resistant to Treg cells. Here, we focus on key mechanisms which render T cells resistant to the suppressive effects of Treg cells. Lastly, we also examine current limitations and caveats of overcoming the inhibitory activity of Treg cells, and briefly discuss the potential to target Treg cell resistance in the context of anti-tumor immunity.

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Section: Reported Cases Of Treg Resistancementioning

confidence: 99%

Turning the Tide Against Regulatory T Cells

et al. 2019

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“…CD28 activation lowers Cbl-b amounts whereas CTLA4 is important for its expression (Li et al 2004). Interestingly, anti-tumor responses in Cbl-b -/mice are more responsive to CTLA4, but not PD1, blockade (Peer et al 2017). In addition, checkpoint inhibtors lead to the upregulation of different classes of T cells against tumors, i.e.…”

Section: How Do Checkpoint Inhibitors Mediate Antitumor Effects?mentioning

confidence: 99%

T cell costimulation, checkpoint inhibitors and anti-tumor therapy

et al. 2020

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The hallmarks of the adaptive immune response are specificity and memory. The cellular response is mediated by T cells which express cell surface T cell receptors (TCRs) that recognize peptide antigens in complex with major histocompatibility complex (MHC) molecules on antigen presenting cells (APCs). However, binding of cognate TCRs with MHC-peptide complexes alone (signal 1) does not trigger optimal T cell activation. In addition to signal 1, the binding of positive and negative costimulatory receptors to their ligands modulates T cell activation. This complex signaling network prevents aberrant activation of T cells. CD28 is the main positive costimulatory receptor on naïve T cells; upon activation, CTLA4 is induced but reduces T cell activation. Further studies led to the identification of additional negative costimulatory receptors known as checkpoints, e.g. PD1. This review chronicles the basic studies in T cell costimulation that led to the discovery of checkpoint inhibitors, i.e. antibodies to negative costimulatory receptors (e.g. CTLA4 and PD1) which reduce tumor growth. This discovery has been recognized with the award of the 2018 Nobel prize in Physiology/Medicine. This review highlights the structural and functional roles of costimulatory receptors, the mechanisms by which checkpoint inhibitors work, the challenges encountered and future prospects.

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“…Cblb -/mice also reject transplanted tumors. The rejection of spontaneous tumors or transplanted tumors is mediated by CD8 + T cells [85][86][87]. Interestingly, Cblb -/-CD8 + T cells are resistant to suppression by CD4 + CD25 + Tregs, TGF-β, or PD-L1 [84,85,87].…”

Section: 3b Cbl-b In Cd8 + T Cell Responses In Tumors-cd8mentioning

confidence: 99%

“…The rejection of spontaneous tumors or transplanted tumors is mediated by CD8 + T cells [85][86][87]. Interestingly, Cblb -/-CD8 + T cells are resistant to suppression by CD4 + CD25 + Tregs, TGF-β, or PD-L1 [84,85,87]. Taken together, these studies indicate that inhibition of Cbl-b by small molecule inhibitors or Cblb siRNA may represent an effective strategy to treat patients with tumors in combination with the current immune check-point blockers such anti-PD-1 or anti-PD-L1.…”

Section: 3b Cbl-b In Cd8 + T Cell Responses In Tumors-cd8mentioning

confidence: 99%

Regulation of immune responses by E3 ubiquitin ligase Cbl-b

Tang

Langdon

Zhang

2019

Cellular Immunology

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Casitas B lymphoma-b (Cbl-b), a RING finger E3 ubiquitin ligase, has been identified as a critical regulator of adaptive immune responses. Cbl-b is essential for establishing the threshold for T cell activation and regulating peripheral T cell tolerance through various mechanisms. Intriguingly, recent studies indicate that Cbl-b also modulates innate immune responses, and plays a key role in host defense to pathogens and anti-tumor immunity. These studies suggest that targeting Cbl-b may represent a potential therapeutic strategy for the management of human immune-related disorders such as autoimmune diseases, infections, tumors, and allergic airway inflammation. In this review, we summarize the latest developments regarding the roles of Cbl-b in innate and adaptive immunity, and immune-mediated diseases.

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Cblb-deficient T cells are less susceptible to PD-L1-mediated inhibition

Cited by 20 publications

References 61 publications

Turning the Tide Against Regulatory T Cells

Turning the Tide Against Regulatory T Cells

T cell costimulation, checkpoint inhibitors and anti-tumor therapy

Regulation of immune responses by E3 ubiquitin ligase Cbl-b

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