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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
A single signal is not enough for T cell activation; a T cell is not activated when the TCR (T cell receptor) binds an antigen-bound MHCI complex. T cell activation requires an additional signal viz. the binding of co-receptors. This second signal has been termed co-stimulation. In T cells, the second signal takes place when CD28 present on T cells binds to CD86 (B7-2) or CD80 (B7-1) expressed by APCs [16–18]. These co-receptors or co-stimulants, when active, act as accelerators that promote the T cell activation and, hence, the immune response. However, it was later discovered that some co-receptors act, in fact, as brakes that reduce the activation of T cells. These brake co-receptors are required, as mentioned above, to avoid an exaggerated and damaging immune response. The brakes inhibitory signaling pathways, are termed the immune checkpoints, and constitute any signal that inhibit priming of T cell activation or any signal that reduce an already initiated T cell response [19].
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.
Understanding the complex microenvironment in oral cancer: the contribution of the Faculty of Dentistry, University of Otago over the last 100 years
Published in Journal of the Royal Society of New Zealand, 2020
Alison Mary Rich, Haizal Mohd Hussaini, Benedict Seo, Rosnah Bt Zain
Discovered by Mechnikoff in the early 1900s, the macrophage was named a phagocyte due to its ability to ‘devour’. Apart from being well-known phagocytes, macrophages and DC are a crucial group of APCs. Their ability to phagocytose and process microbial agents, foreign antigens, cell debris and dying cells, process and present protein antigens to naïve lymphocytes in secondary lymphoid organs is crucial to immune homeostasis and allowed them to be characterised as APCs (Male et al. 2006). This role is important in order to activate differentiation and clonal expansion of T cells (Bluestone et al. 2009). Therefore, APCs have a significant transitional or bridging role between innate and adaptive immunity. APCs respond to a wide variety of non-specific inflammatory mediators or to stress signals produced by cancer cells through membrane bound or vesicular Pattern Recognition Receptors (PRRs) such as Heat Shock Proteins (HSPs), and TLRs (Toll-Like Receptors) (Duffield 2003). Upon encountering foreign antigen or tumour cells, they will phagocytose protein or tumour antigens and then proceed to secondary lymphoid organs for antigen presentation. While in the lymph nodes, antigen presentation to lymphocytes occurs and produces clonal expansion of CD4+ and CD8+ T cells, as well as the recently discovered subsets of Th17 and Tregs (McCluskey 2011). Through interleukin (IL)-12, CD80 and other co-signalling molecules, priming of naïve T cells occurs enabling them to become specific cytotoxic T cells (CD8+ CTLs). These cells then enter the circulation where they will recognise and destroy target cells. In tumours, macrophages are known as tumour-associated macrophages (TAMs), first discovered by Mantovani et al. (1986). The role of TAMs has been unclear, however most reports acknowledge that TAMs enhance the progression of tumours and can inhibit adaptive immune responses to cancer (Allavena et al. 2008). The presence of TAMs was associated with poor prognosis in multivariate analyses of several cancers (Ho et al. 2008; Zhu et al. 2008). They are recruited to the region of the tumour in response to the secretion of interferon (IFN)γ where, depending on the cytokines present, can be induced to differentiate into: (1) M1 type of macrophages which express IL-12 and tumour necrosis factor (TNF) supporting a Th1 response or (2) M2 type of macrophages which secrete IL-10 and IL-4 supporting a Th2 response (Martinez et al. 2008; Pinto et al. 2019). Most TAMs observed in the cancer environment resemble M2-polarised macrophages (Mantovani et al. 2004; Mosser and Edwards 2008) and instead of being induced by IFNγ, they are associated with Th2 cytokines, such as IL-4 and IL-10 (Cassetta and Pollard 2018). It is not clear as to the regulatory mechanism which governs the polarisation of these macrophages, particularly in the OSCC TME. As mentioned earlier, our research group has previously assessed macrophages in OSCC tissues and shown that there were more CD68+ macrophages in OSCC compared to inflammatory control tissue (Hussaini 2013).