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The Scientific Basis of Medicine
Published in John S. Axford, Chris A. O'Callaghan, Medicine for Finals and Beyond, 2023
Chris O'Callaghan, Rachel Allen
B and T lymphocytes equip the adaptive immune response with its specificity, diversity and memory. The initial activation of naive T cells requires recognition of antigen by the T-cell receptor (TCR) and sufficient co-stimulatory signalling and appropriate cytokines. Co-stimulation is regulated by proteins which serve as immune checkpoints to restrain the activation of adaptive immunity. Successful activation of naive T cells leads to the proliferation of a population of effector cells which, in the case of helper T cells (THcells), support the functions of B cells and cytotoxic T cells (CTLs).
Immunopathology
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
Recall from Chapter 6 that co-stimulation is an important component of antigen presentation and T cell activation. T cells require specific signals in addition to peptide + MHC class II in order to be activated. It is not yet clear whether in some of the situations above, non-professional APCs may possess co-stimulatory activity. Alternatively, “bystander” professional APCs may participate in some fashion in T cell activation by somatic cells which cannot themselves provide co-stimulation.
Mitochondrial Dysfunction, Immune Systems, Their Diseases, and Possible Treatments
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Elise Jacquin, Eric Hervouet, Michaël Boyer-Guittaut
The efficiency of treatments using adoptive T-cell transfer in case of metastatic cancers has also been shown to be linked to the metabolic status of the transferred T-cells. Indeed, highly glycolytic T-cells showed shorter life expectancy and lower anti-tumor activity in the patient than the highly respiratory ones which presented longer persistence in vivo.89 Therefore, sorting T-cells according to their metabolic activity before transfer could improve treatment efficiency in term of anti-tumor activity as well as duration. Furthermore, Buck and collaborators recently showed that pharmacological enforcement of mitochondrial fusion improved the anti-tumor functions of CD8 T-cells upon adoptive transfer.14 These data suggest a potential interest in targeting mitochondria in the context of cellular immunotherapy of cancer. In line with this, 4-1BB co-stimulation appears like an interesting strategy to enhance CD8 T cell-mediated antitumor responses through mitochondrial function improvement in the context of both T cell adoptive transfer and PD-1 blockade.48
An adjuvant-containing cDC1-targeted recombinant fusion vaccine conveys strong protection against murine melanoma growth and metastasis
Published in OncoImmunology, 2022
Mohammad Arabpour, Sanchari Paul, Hanna Grauers Wiktorin, Mustafa Kaya, Roberta Kiffin, Nils Lycke, Kristoffer Hellstrand, Anna Martner
Dendritic cells (DC) play a key role in anti-tumor defense by virtue of their supreme capacity to (i) take up antigen and migrate to draining lymph nodes for priming of CD4+ and CD8+ T cells, (ii) provide co-stimulation that regulates T cell priming and differentiation, and (iii) generate chemoattractants that recruit anti-tumor effector cells.1 These features have inspired the development of immunotherapies that target DC aiming at achieving effective and durable T cell-mediated immunity against cancer.2 In the clinical setting, such strategies have mostly comprised of the adoptive transfer of patient-derived DC, where autologous DC or precursor cells are treated ex vivo with cytokines to induce their differentiation and maturation.3,4 In patients, such DC-targeted anti-tumor strategies may entail local and systemic T cell activation, but objective anti-tumor responses have hitherto been unimpressive.5 The limited clinical benefit of DC-centered approaches has been attributed to insufficient antigen presentation or co-stimulation or reduced survival of DC in the malignant microenvironment.6,7 The lack of efficient T cell priming of anti-tumor immunity calls for additional or improved DC-based strategies.
CAR-T cells for cancer immunotherapy—the barriers ahead and the paths through
Published in International Reviews of Immunology, 2022
Qiqi Zhang, Cheng Zu, Yongxian Hu, He Huang
To surmise this hurdle, second-generation CARs incorporated a co-stimulatory signaling domain with CD3ζ activating domain, which showed better T cell-mediated tumor eradication. Different co-stimulation domains endow CAR-T cells with distinct properties, including metabolic pathways, persistence, differentiation, cytotoxicity, and etc. The most widely studied co-stimulation domains are CD28 and 4-1BB (CD137). CAR-T cells with 4-1BB domains are prone to differentiate into central memory T cells (TCM cells) which exhibit longer persistence and enhanced oxidative metabolism, whereas CD28 co-stimulation yield a more potent, yet inclined to exhaustion phenotype with increased dependence on glycolysis pathway [17]. Other than CD28 and 4-1BB, several other co-stimulation domains are under investigation, such as inducible T cell co-stimulator (ICOS) [18], OX40 [19], MyD88 and CD40 [20].
Emerging immune checkpoint inhibitors for the treatment of hepatocellular carcinoma
Published in Expert Opinion on Emerging Drugs, 2021
Landon L. Chan, Stephen L. Chan
The mainstream immune checkpoint inhibitors currently available in the market belong to either the class of anti-CTLA4 or anti-PD-1/PD-L1. CTLA-4 is a negative regulator of T-cell activity. In the priming phase, it is well understood that activation of T-cell requires two signals [35]. The first signal occurs when the cognate antigen on the MHC molecule of antigen presenting cells is presented to the T-cell receptor on the naïve T-cells resting in the draining lymph nodes. This activates T-cells but is inadequate to maintain its activation so a second signal is required. The best studied example is the interaction between CD80/86 molecules on the antigen presenting cells and the CD28 molecule on the naïve T-cells. The co-stimulation lowers significantly the threshold for T-cell activation, allowing the adaptive immune system to engage in clearing foreign antigens (e.g. bacteria, tumor) much more efficiently. On the other hand, upon activation, naïve T-cells also begin to express repressive molecules such as CTLA-4 on their surface. This provides a negative feedback mechanism to allow T-cells to be inactivated when foreign antigens have been cleared out. CD80/86 on the antigen presenting cells have a 10-fold higher binding affinity to the CTLA-4 than CD28. Therefore, as more naïve T-cells are being activated initially by the CD80/86:CD28 co-stimulation, more CTLA-4 are subsequently being presented on the cell surface. Consequentially, more CD80/86 bind to the inhibitory CTLA-4, eventually turning off the immune system to prevent the development of an overactive immune response.