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      MRC Human Immunology Unit

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      Science Impact, Ltd.

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          Abstract

          Research carried out in my laboratory is aimed at gaining a better understanding of the mechanisms that control the cell-cell interplay required for optimal expansion and activation of tumour-specific T cell populations and to apply this knowledge to the development of better treatment strategies in cancer patients. Research in my laboratory is divided into the following complementary areas:? Analysis of tumour-specific immune responses in cancer patients ? The role of the tumour micro-environment in hampering tumour-specific immune responses;? Structural, kinetic and functional analyses of invariant NKT (iNKT) cell activation;? Clinical trial vaccine programme in cancer patients.My laboratory is analysing several complementary aspects of the immune responses against solid tumours (ovarian and endometrial cancers, melanoma, bladder and glioblastoma). The ultimate goal is to stratify patients for immunotherapy and establish strategies for sensitisation of non-responders. Cancer immunology is an area of cancer research that is gaining tremendous momentum. Recent advances in the use of monoclonal antibodies and adoptive cellular therapy to treat cancer by modulating the immune response have led to unprecedented responses in patients with advanced stage tumours. The results of these clinical studies have highlighted the therapeutic potential of harnessing cancer patients? own tumour-specific immune responses, which are often hampered by inhibitory signals activated by tumour cells. However, responses to immunotherapy are heterogeneous, and patient care could be substantially improved by a better understanding of how and why responses to these and other therapies vary. There is a need for investigation of the molecular and immunological basis of response and resistance to therapy. Addressing this challenge requires the detailed analyses of patient samples taken at multiple time points before, during and after treatments. We are establishing such a programme in the context of a novel innovative clinical study of combination immunotherapy in bladder cancer patients and in melanoma patients. The clinical study has been specifically designed to set up an experimental medicine discovery platform that can be used in the future for other studies. It will generate valuable resources to carry out many strands of molecular analysis of patient samples, including genomic, epigenomic, proteomic, immunological and histological studies. In addition, as a collaboration with Prof. Ahmed Ahmed (WIMM) we are interrogating the T Cell Receptor repertoire in ovarian cancer patients and characterising T cell specificity. Modulation of T cell activity by tissue stroma and tumour micro-environment We have recently developed a programme focussed on the analysis of the mechanisms by which tumour cells can evade immune responses and have focused on two aspects: expression of amino acid degrading enzymes; and the ability of tissue stroma to modulate the expression of tissue homing receptors expressed by T lymphocytes. i) Modulation of the amino acid transporter profiling by tumour cells expressing amino acid degrading enzymes. The ability of the enzyme indoleamine 2,3-dioxygenase (IDO), expressed by a broad range of tumour cells, to convert the essential amino acid tryptophan to kynurenines has been shown to be one of the common mechanisms by which tumours hamper tumour-specific immune responses (37). We have described the expression of a novel tryptophan transporter by IDO-positive human and mouse tumour cells (Silk et al., J Immunol, 2011) (Timosenko et al., Cancer Res, 2016); this provides tumour cells with strategies to evade immune surveillance and survive in a tryptophan-depleted environment.ii) Secretion of Arginase II by Acute Myeloid Leukaemia (AML) blasts. We have shown that AML blasts alter the immune microenvironment through enhanced arginine metabolism (Mussai et al., Blood, 2013). Release of Arginase II from AML blasts results in suppression of T-cell proliferation and reduced proliferation of human CD34+ haematopoietic progenitors. These results strongly support the hypothesis that AML creates an immunosuppressive microenvironment that contributes to the pancytopenia observed at diagnosis.Structural, Kinetic and Functional Analyses of iNKT Cell Activationi) Identification of a novel family of iNKT cell agonists. We have previously shown that the non-glycosidic CD1d-binding lipid threitolceramide (ThrCer) activates murine and human iNKT cells (Jukes et al., Eur J Immunol, 2016). As a collaboration with Gurdyal Besra (Birmingham), over the last 5 years we have developed a medicinal chemistry programme to further optimise this family of iNKT cell agonists. The results of these studies have led to the identification of a novel compound incorporating the headgroup of ThrCer into a conformationally more restricted 6-membered ring (ThrCer6), which resulted in a significantly more potent non-glycosidic iNKT cell agonist. In particular, ThrCer 6 was found to promote strong anti-tumour responses and to induce a more prolonged stimulation of iNKT cells than does the canonical ŕ-galactosylceramide (ŕ-GalCer). Enhanced T-cell responses were achieved at lower concentrations compared with ŕ-GalCer both in vitro, using human iNKT-cell lines and in vivo, using C57BL/6 mice. Collectively, these studies describe novel non-glycosidic ThrCer-based analogs that we are developing as clinically relevant iNKT-cell agonists with improved potency. ii) Role for cortical actin in controlling the nanoscale distribution of CD1d molecules on the cell surface and in activating iNKT cells. Using super-resolution microscopy, we have shown that CD1d molecules form nanoclusters at the cell surface of Antigen Presenting Cells (APCs), and demonstrated that the size and density of CD1d nanoclusters is constrained by the actin cytoskeleton. We have demonstrated that either deletion of CD1d cytosolic tail or destruction of the cortical actin increases the mobility of CD1d molecules on the cell surface, resulting in the formation of larger and more densely packed CD1d molecules, which in turn results in significantly enhanced activation of iNKT cells. Importantly, and consistent with iNKT cell activation during inflammatory conditions, exposure of APCs to the Toll-like receptor 7/8 agonist R848 also increases nanocluster density and iNKT cell activation (Torreno-Pina et al., Proc Natl Acad Sci USA, 2016). These results define a previously unidentified mechanism that modulates iNKT cell autoreactivity, by demonstrating that the spatio-temporal distribution of CD1d molecules, controlled by cortical actin, modulates activation of iNKT cells. Translational Programme.Anti PD1 Ab treatment of bladder cancer patients. In the next few months we will start a randomized marker lesion clinical trial in non-muscle invasive bladder cancer patients treated with the anti PD1 Ab, injected either systemically or intravesically. This is the first marker lesion study with immune checkpoint inhibitors, based on the collection of tumour marker lesions left in the bladder after primary surgery and then removed during and after completion of the trial. This marker lesion study will provide us with the opportunity to study changes in the transcriptomic profiling of the tumour mass before, during and after the trial. In addition, this is the first time that the immune check point inhibitors will be injected in the peri-tumoural area.

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          Journal
          Impact
          impact
          Science Impact, Ltd.
          2398-7073
          August 08 2017
          August 08 2017
          : 2017
          : 6
          : 42-44
          Article
          10.21820/23987073.2017.6.42
          © 2017

          This work is licensed under a Creative Commons Attribution 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

          Earth & Environmental sciences, Medicine, Computer science, Agriculture, Engineering

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