Savelyeva, Natalia - University of Southampton

个人简介

Dr Natalia Savelyeva graduated from Moscow State University, Russia, with a degree in Biochemistry and Virology. Subsequently she completed her PhD at University of East Anglia in 1999 under supervision of Dr I Gibson. She then moved to Southampton to continue her training in the laboratory of Prof F.K. Stevenson where she was working on the development DNA fusion vaccines against hematologic malignancies. After completing her post-doctoral training she became an independent investigator in CSU, Faculty of Medicine, but continued working closely with Prof Stevenson. In 2013 she was appointed as a Lecturer in Cancer Immunology in CSU. Natalia’s main focus has been to develop novel conjugate cancer vaccines based on plant viral particles and to understand how cancer vaccines operate in the tolerogenic cancer setting. Aiming to take novel cancer vaccines into clinical setting, Natalia works in close collaboration with Prof Ottensmeier, a consultant oncologist with a core academic interest in early translation of immunotherapeutic strategies into the clinic. A second line of research has concerned the maintenance of memory B-cell responses and has led to an increased understanding of IgG and IgM memory B cells and the role of T-cell help in guiding memory B cells towards responsiveness to antigen rather than tolerance.

研究领域

Cancer vaccines With cancer vaccines starting to deliver on their long-awaited promise, novel powerful vaccines are required. Cancer antigens by themselves are weakly immunogenic because of central and peripheral tolerance. Together with Prof Freda Stevenson (CSU, Southampton) we have developed conjugate vaccines where weak cancer antigens are fused to strong immunogenic carries derived from pathogens to improve cancer vaccine immunogenicity (Figure 1). Both Fragment C of Tetanus toxoid and the coat protein of a plant virus have been used as immunogenic carriers. Conjugation engages the CD4 T-cell repertoire specific for these foreign antigens, and this leads to generation of cancer antigen-specific antibody and CD8+ T cells to attack cancer. These principles were initially used in DNA vaccines targeting a number of antigens in both solid tumours and hematologic malignancies, which are now in clinical trials in Southampton (Prof Ottensmeier, CSU Southampton). This conjugation strategy now has been applied to several other novel cancer vaccines modalities (Figure 1). Our novel conjugate vaccine for breast cancer has been developed in collaboration with Icon Genetics (Halle Germany) and utilises plant expression systems developed by Icon genetics for vaccine manufacturing. Together with Prof Ottensmeier and Dr E. Copson (CSU, Southampton) we are now planning to take this vaccine into phase I clinical trial in patients with metastatic breast cancer. Another novel vaccine design based on plant viral particles is also now being developed by the group (Figure 1). Maintenance of B cell memory Memory B cells express surface antigen receptors of either IgG or IgM isotype and are programmed to rapidly generate antibodies upon antigen recall. These antibody are essential for clearing infections and potentially for eliminating cancers. We have identified the critical factors for maintenance of memory B cells. In particular, we found that both IgG and IgM memory B cells require T-cell helper signals for responsiveness to antigen (Figure 2). Remarkably, in the absence of T-cell help high affinity IgG+ memory B cells become permanently and irreversibly unresponsive through deletional mechanisms when challenged by antigen (Figure 2). This involved cross-linkage of the B-cell receptor, but was largely independent of the inhibitory receptor FcγRIIB on B cells. In marked contrast, low affinity IgM+ memory B cells escape deletion and upon adoptive transfer are responsive to antigen stimulation when help is provided. Collectively, CD4+ T-cell help together with affinity for the antigen, guides memory B cells towards responsiveness rather than tolerance. These findings are of relevance to the maintenance of B-cell responses to antigen in the absence of T-cell help which occur in chronic infection and cancer. Together with Dr A. Allen (CSU, Southampton) and Dr K-M. Toellner (University of Birmingham, U.K.) we are now conducting a study to understand the nature of B-cell tolerance using a novel model of memory B cells we have recently developed.

近期论文

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Gene expression analysis of TIL rich HPV-driven head and neck tumors reveals a distinct B-cell signature when compared to HPV independent tumors - Wood, Oliver, Woo, Jeongmin, Seumois, Gregory, Savelyeva, Natalia, Mccann, Katy J., Singh, Divya, Jones, Terry, Peel, Lailah, Breen, Michael S, Ward, Matthew, Garrido Martin, Eva, Sanchez-Elsner, Tilman, Thomas, Gareth, Vijayanand, Pandurangan, Woelk, Christopher H., King, Emma and Ottensmeier, Christian Published:2016Publication:OncotargetPage Range:1-17doi:10.18632/oncotarget.10788PMID:27462861 IL-4 enhances expression and function of surface IgM in CLL cells - Aguilar-Hernandez, Maria M., Blunt, Matthew, Dobson, Rachel, Yeomans, Alison, Thirdborough, Stephen, Larrayoz, Marta, Smith, Lindsay, Linley, Adam, Strefford, Jonathan C., Davies, Andrew, Johnson, Peter, Savelyeva, Natalia, Cragg, Mark, Forconi, Francesco, Packham, Graham, Stevenson, Freda K. and Steele, Andrew J. Published:2016Publication:BloodPage Range:1-25doi:10.1182/blood-2015-11-682906PMID:27002119 A plant expressed conjugate vaccine breaks CD4 tolerance and induces potent immunity against metastatic Her2+ breast cancer - Savelyeva, Natalia, Ottensmeier, Christian, Stevenson, Freda, Allen, Alex and Harden, Elena Published:2016Publication:OncoimmunologyPage Range:1-38doi:10.1080/2162402X.2016.1166323 Plant virus particles carrying tumour antigen activate TLR7 and induce high levels of protective antibody - Jobsri, Jantipa, Allen, Alex, Rajagopal, Deepa, Shipton, Michael, Kanyuka, Kostya, Lomonossoff, George P., Ottensmeier, Christian, Diebold, Sandra S, Stevenson, Freda K. and Savelyeva, Natalia Published:2015Publication:PLoS ONEVolume:10, (2)Page Range:1-16doi:10.1371/journal.pone.0118096PMID:25692288