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Title: Defining the effects of CD28 superagonist and TGF-β on T cell function and metabolism
Author: Thaventhiran, Thilipan
ISNI:       0000 0004 5363 076X
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2014
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Immunomodulatory monoclonal antibodies (mAbs) indicated for the treatment of cancer, inflammatory and autoimmune diseases or to prevent organ transplant rejection, mostly target cell surface molecules expressed by immune cells including T cells. The presence of immunosuppressive molecules during disease progression can hinder the activity of immune cells. Tumour-induced immunosuppression enables disease progression and various strategies are being developed to enhance the anti-tumour responses of cytotoxic T cells. Activation of effective effector responses require resetting of metabolic activity to fit energy and anabolic needs. While the benefits of exploiting immunomodulatory mAbs for therapy are substantial, it is also clear that use of these biologics may be accompanied by adverse effects such as cytokine release, immunosuppression, infections and autoimmunity. Significant focus in recent times has been on assessing the potential of immunomodulatory mAbs to induce enhanced cytokine release but much less attention has been paid to other aspects of T cell biology including non-physiological activation phenotype/functions, migration characteristics and metabolism. An improved understanding of these parameters may assist in accurately predicting the propensity of new mAbs to induce serious adverse effects. Superagonistic CD28-specific monoclonal antibody (CD28SA) is one such immunomodulatory monoclonal antibody which is a potent stimulator of T cells, originally intended for the management of B cell chronic lymphocytic leukaemia and rheumatoid arthritis. Human volunteers who received humanized CD28SA (TGN1412) as part of a first-in-man trial experienced life-threatening cytokine release syndrome. Follow-up studies revealed aberrant activation of effector memory T cells (TEM) contributed towards the adverse reaction. The biopharmaceutical industry is actively pursuing development of T cell immunostimulatory mAbs and there is a significant need to improve the understanding of and accurately predict the propensity of a new mAb to drive excessive T cell activation. Therefore, one of the main aims of the study discussed in this thesis was to determine mechanism/s underlying the hyperactive phenotype of CD28SA-activated TEM. Observations in the current study revealed activation of TEM by CD28SA upregulated the expression of activation markers such as CD137 and HLA-DR, but failed to express co-inhibitory receptor, PD-1. This led to the lack of PD-1-mediated regulation of aberrant TEM activation. In addition, CD28SA-activated TEM expressed elevated levels of LFA-1 and CCR5 receptors, and displayed increased migratory capacity. Subsequent studies highlighted increased metabolic demand of CD28SA-activated TEM. The hyperactive cells with increased proliferative capacity exhibited distinct metabolic profile characterized by increased glycolysis and lipogenesis. These findings have profound implications for strategies aiming at understanding and predicting the safety profile of immunostimulatory mAbs. Deployment of immunosuppressive strategies, including TGF-β secretion by tumours to render immunostimulatory mAbs-mediated anti-tumour responses ineffective is well studied. The other study discussed in this thesis aimed to delineate the effects of oxidative stress in TGF-β-induced suppression of antigen-specific cytotoxic T cell responses. This study showed antigen-specific T cells exposed to TGF-β down regulate CD25 and LAG-3 (co-inhibitory T cell receptor) expression, secrete lower levels of IL-2 and IFN-γ, and reduced glycolysis. In addition, mitochondrial reactive oxygen species (MitoROS) scavenger rescued the effector functions such as proliferation and IFN-γ secretion of stimulated T cells that were inhibited by TGF-β. Our findings demonstrate that relief of TGF-β-induced oxidative stress restores the effector function of CD8+ cytotoxic T cells. Based on the current findings it would be potentially beneficial to supplement immunotherapies with antioxidants to counteract the immunosuppressive effects of tumour-derived TGF-β to help restore CD8+ T cell-mediated anti-tumour function. The findings presented in this thesis may help with defining key T cell biomarkers based of efficacy and hazard associated with immunomodulation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Q Science (General) ; RM Therapeutics. Pharmacology