Oncogenesis and Metastasis
Karl H. Pang, Nadir I. Osman, James W.F. Catto, Christopher R. Chapple in Basic Urological Sciences, 2021
Immune checkpoint blockade forms the basis of immunotherapy.PD-L1 (programmed cell death protein ligand 1) on tumour cells.PD-1 (programmed cell death protein 1) on T-cells.PD-L1 and PD-1 binding results in T-cell deactivation.PD-L1 and/or PD-1 inhibitor are used in metastatic bladder/renal cancers.CTLA-4 (cytotoxic T-lymphocyte associated protein 4).Expressed by regulatory T-cells.CTLA-4 inhibitors are used in metastatic renal cancer.Inhibitors restore tumour-specific T-cell immunity.
Future therapies in lung transplantation
Wickii T. Vigneswaran, Edward R. Garrity, John A. Odell in LUNG Transplantation, 2016
CD28 belongs to the immunoglobulin superfamily and is expressed on the surface of T cells. It binds to B7.1 (CD80) and B7.2 (CD86) on APCs to facilitate T-cell activation and proliferation. Specifically, interaction between CD28 and B7 results in increased T-cell proliferation, production of interleukin-2 [IL-2], expression of the antiapoptotic protein Bcl-xL, and increased expression of CD154 (discussed later) on T cells. Blocking these effects would seemingly be desirable in terms of allograft acceptance. However, in addition to binding CD28, B7 (CD80/CD86) is also able to bind with higher avidity and affinity to CTLA4 on T cells. This interaction, in contrast to the interaction between CD28 and B7, inhibits T-cell proliferation and has peripheral tolerogenic effects, the mechanisms of which are not fully understood. CTLA4 expression is induced in activated T cells (presumably as a negative feedback mechanism), and it is expressed constitutively in certain regulatory T cells. Blocking the tolerogenic effects of interaction of CTLA4 with B7 is not desirable from the standpoint of allograft acceptance. However, the implications of interaction between CTLA4 and B7 were not known when the initial attempts to block CD28-B7 began.
Great strides in precision medicine: Personalized oncology and molecular diagnostics
Priya Hays in Advancing Healthcare Through Personalized Medicine, 2017
Pembrolizumab and ipilimumab are targeted therapies known as immune checkpoint inhibitors. Both agents were designed to harness the body’s immune system to fight cancer. However, the drugs have different molecular targets and affect the immune response to cancer in different ways. Ipilimumab, a monoclonal antibody, binds to a protein called CTLA4, which is found on the surface of T cells. CTLA4 is a checkpoint protein that normally acts to keep immune responses in check to prevent overly strong responses that might damage normal cells as well as abnormal cells. The binding of ipilimumab to CTLA4 relieves this suppression. Ipilimumab was the first immune checkpoint inhibitor to be approved by the FDA (in 2011) to treat advanced melanoma (National Cancer Institute website).
Immunotherapy of High Risk Non-Muscle Invasive Bladder Cancer
Published in Expert Review of Clinical Pharmacology, 2021
Michael Ahdoot, Dan Theodorescu
Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) is a cell surface molecule expressed on multiple T cell types including cytotoxic and T regulatory cells. CTLA-4 activation typically results in an upregulation of T regulatory cell function and a suppression of cytotoxic T-cell activity. During normal cellular function, antigen presenting cells (APCs), such as dendritic cells, B cells, and macrophages, present antigens on MHC I molecules to T cells. The antigen presenting MHC I binds to the T cell receptor creating an activation signal for the T cell. Simultaneously, the APC cell surface peptide, B7-1(also known as CD-80) will bind the T cells CD-28, acting as a co-stimulator for CD4 T cell activation [47–49]. However, after activation T cells can produce surface CTLA-4 receptors which compete to bind APCs’ B7-1 sites preventing further B7-1 and CD-28 interactions, which in turn prevent T cell activation [50]. CTLA-4 inhibitors such as Ipilimumab and Tremelimumab are monoclonal anti-CTLA-4 antibodies which neutralize the effect of CTLA-4 binding B7-1 and prevent the T cell suppressive effects of CTLA-4 interaction with B7-1 on the antigen presenting cell [51] (Figure 2).
Immune-checkpoint blockade of CTLA-4 (CD152) in antigen-specific human T-cell responses differs profoundly between neonates, children, and adults
Published in OncoImmunology, 2021
Aditya Arra, Maximilian Pech, Hang Fu, Holger Lingel, Franziska Braun, Christian Beyer, Myra Spiliopoulou, Barbara M. Bröker, Karen Lampe, Christoph Arens, Katrin Vogel, Mandy Pierau, Monika C. Brunner-Weinzierl
The immune system has developed sophisticated mechanisms to regulate, or more precisely to inhibit, the unintended activation of T-cells. Cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4) is an inhibitory receptor on T-cells and its expression and function is intrinsically linked with T-cell activation. CTLA-4 is expressed on the surface of T-cells following TCR engagement, with its expression peaking 2–3 days after activation. The receptor counteracts TCR and CD28 mediated signals to suppress activation of T-cells.9 Studies in in vitro and in vivo mouse models displayed that blockade of CTLA-4 signaling leads to an increase in T-cell proliferation and Th1-like cytokine production. Furthermore, it has been shown that CTLA-4 blockade affects in particular the proinflammatory cytokines IL-2 and IFNγ.10,11 Th2 responses are only impacted by CTLA-4 inhibition when not controlled by regulatory T-cells.12 Ipilimumab a monoclonal antibody (MAb) against CTLA-4 was the first immune-checkpoint inhibitor to be approved for clinical use. It is applied to enhance immune responses in adult cancer patients.13–15 Ipilimumab is used especially in immunogenic cancers such as advanced melanoma, and a pooled analysis of long-term follow up studies shows an overall survival rate of 22%.16
Abatacept for the treatment of rheumatoid arthritis
Published in Expert Review of Clinical Immunology, 2019
Manuel Pombo-Suarez, Juan J. Gomez-Reino
CTLA4 is a molecule whose expression is induced upon T-cell activation. It competes with CD28 interfering with its ligation to CD80/86. This in turn down-regulates T-cell activation (Figure 1(b)). With this in mind, CTLA4 became an interesting way to modulate immune response in different disorders [10,11]. Administration of CTLA4–Ig prevented and also ameliorated collagen-induced arthritis [12]. A direct consequence of this line of investigation was the development of abatacept – a soluble, fully human, recombinant fusion protein composed of the Fc region of IgG1 fused to the extracellular domain of CTLA4. Therefore, abatacept selectively modulates the CD80/CD86:CD28 co-stimulatory signal needed for full T-cell activation and prevents the production of cytokines and downstream immune responses in RA. Downregulation of T-cell activation by abatacept does not involve regulatory T cells, not only that, in vivo studies have demonstrated a general decrease or regulatory T cells after treatment with abatacept [13].
Related Knowledge Centers
- Cd80
- Cd86
- Cluster of Differentiation
- Regulatory T Cell
- Immune System
- T Cell
- Cluster of Differentiation
- Receptor
- Immune Checkpoint
- Antigen-Presenting Cell
- Gene