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Delivery of Immune Checkpoint Inhibitors Using Nanoparticles
Published in Hala Gali-Muhtasib, Racha Chouaib, Nanoparticle Drug Delivery Systems for Cancer Treatment, 2020
Abdullah Shaito, Houssein Hajj Hassan
The first protein to be identified as an immune checkpoint molecule is CTLA-4 (cytotoxic T lymphocyte antigen-4). In 1987, a cDNA expressed in T cells, CTLA-4 (CD152), was cloned in the laboratory of Pierre Golstein [22]. CD28 and CTLA-4 were found to be structurally related and belong to the immunoglobulin superfamily. The function of CTLA-4 was unknown, but later it was found that CTLA-4 protein resides inside inactive T cells and rapidly translocates to the cell plasma membrane following T cell stimulation [23, 24]. Furthermore, CTLA-4 was found to recognize and bind CD80, in a similar way as CD28 but with higher affinity [25]. As a result, it was believed that CTLA-4 had a costimulatory effect on T cells that is similar to CD28. Subsequently, it was shown that CTLA-4 was in reality a negative regulator of T cell stimulation [26, 27]. Later on, the ctla-4 gene was knocked-out in mice, the knock-out mice developed very severe autoimmune symptoms due to excessive T cell proliferation [28, 29]. Consequently, it became clear that CTLA-4 acts as a co-inhibitory molecule and that the response of T cells to stimulation is regulated not only by CD28 costimulatory signals, but also by CTLA-4 inhibitory signals.
Host Response to Biomaterials
Published in Claudio Migliaresi, Antonella Motta, Scaffolds for Tissue Engineering, 2014
Sangeetha Srinivasan, Julia E. Babensee
TCRs recognize peptide fragments of antigens bound to MHC molecules. Naive TH cells require a second signal for generation of protective effector functions post TCR stimulation.95109 This second signal is provided by ligation of costimulatory molecules with B7 molecules on APCs. Upon APC maturation, CD80 and CD86 expressions are upregulated, thus supporting their immunostimulatory ability.111 The third signal of the cytokine environment polarizes T-cells responses. Absence of the second signal leads to T-cell anergy. T-cell polarization, for example, toward TH1 or TH2 phenotypes is achieved in response to secreted IL-12 or IL-4. Regulatory T-cells or Tregs with CD4+ CD25+ CTLA4+ or TGF-^-induced CD4+ CD25- FoxP3+112 have the ability of resolving immunity and promoting tolerance with specificity to antigen. The T-lymphocyte antigen 4 (CTLA4), a molecule homologous to CD28, binds to costimulatory B7 molecules.113114
Enzymes for Prodrug-Activation in Cancer Therapy
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Higher generation CARs are additionally equipped with costimulatory molecules such as CD27, CD 28 or CD137. Co-stimulation is essential for T cell proliferation, differentiation, and survival and determines significantly the result of a T cell’s encounter with an antigen. Co-stimulation signals are generated from the interaction of receptors on the T cells’ surface with ligands on antigen-presenting cells. T cell stimulation by CD28 (the receptor for CD80 (B7.1) and CD86 (B7.2) proteins) is among others involved in the production of various interleukins (e.g., IL-2, IL-6). CD80 expression is upregulated in antigen presenting cells (APCs) via Toll-like receptors, whereas CD86 expression on APCs is constitutive. However, CD80 and CD 86 are missing in many cancer cells with the consequence to fail to respond to their specific antigen (T cell anergy) so that co-stimulation is indispensable for full T-cell activation which is achieved by combining the intracellular signaling domain of CD28 to CD3ζ in one polypeptide chain of the same second-generation CAR. In addition, costimulatory molecules like CD 137, a member of the tumor necrosis factor receptor (TNFR) superfamily family expressed on activated CD8+ T cells can be integrated in first- or second-generation CARs to give a third-generation one. Altogether these CAR-modifications serve to preserve survival and prolong polyclonal expansion of engineered T cells contributing to an increased amplification which results in prolonged T-cell persistence and an improved anti-tumor attack (Chmielewski et al., 2013). According to Sommermeyer et al. (2016) chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ (T helper cells) subsets confer superior antitumor reactivity in vivo.
Nanobodies targeting the interaction interface of programmed death receptor 1 (PD-1)/PD-1 ligand 1 (PD-1/PD-L1)
Published in Preparative Biochemistry & Biotechnology, 2020
Biyan Wen, Lin Zhao, Yuchu Wang, Chuangnan Qiu, Zhimin Xu, Kunling Huang, He Zhu, Zemin Li, Huangjin Li
Programmed cell death protein (PD-1) is a member of the CD28 receptor family expressed on the surface of T cells, T regulatory cells (Tregs) and B cells.[1–3] PD-1 has two major ligands, termed programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2). The binding of PD-1 to its ligand inhibits the proliferation and activation of T cells and the secretion of related cytokines. Under normal conditions, PD-1 combined with PD-L1 or PD-L2 inhibits the activation and function of T cells, which in turn upregulates Tregs[4,5] leading to a loss of autoimmunity and enhanced self-tolerance.[6–9] PD-L1 is expressed in normal human tissues and organs but is overexpressed on the surface of various tumor cells. PD-L2 is also been detected in a small number of B-cell lymphomas9.[10] In the normal immune system, the primary role of PD-1/PD-L1 signaling is to maintain the balance of protective immunity and immune tolerance. In the tumor microenvironment, PD-1/PD-L1 signaling prevents effector T cells from identifying and killing tumor cells, resulting in immune cell escape.[1–3]
A targeted graphene nanoplatform carrying histamine dihydrochloride for effective inhibition of leukemia-induced immunosuppression
Published in Journal of Biomaterials Science, Polymer Edition, 2018
Kondareddy Cherukula, Md. Nurunnabi, Yong Yeon Jeong, Yong-Kyu Lee, In-Kyu Park
The majority of leukemia patients experience relapses with a very low survival rate. At present, many consolidation therapies are employed for complete eradication of residual leukemic cells, such as the administration of repeated cycles of anthracycline and cytarabine to leukemia patients [1]. Natural killer (NK) cells and T cells possess the most potent anti-leukemic activity and can induce apoptosis selectively in malignant cells by the recognition of various inhibitory and activating receptors [2]. Interleukin-2 (IL-2), which is a T cell and NK cell activating cytokine, was recently tested in a clinical study for prevention of relapse and did not yield any positive results [1]. Many mechanisms have been proposed for the possible failure of lymphocyte mediated anti-leukemic activity, such as radical-dependent inhibition of cytotoxic lymphocytes, deficiency in NK cell receptors, impaired interaction between CD28 antigen and acute myeloid leukemia (AML) blasts, and T-cell apoptosis induced by the Fas-ligand [3–5].