Research Of Glycoprobe Based Cancer Immunotherapy

With the increasing cancer mortality,effective therapies against cancers are of high clinical value.Conventional therapies for cancers,such as radiation and chemotherapy,despite have initial responses,are limited by relapse and resistance in patients with advanced cancer after prolonged treatment.Tumor cells can change their surfaces to avoid immunological surveillance.As such,People tumor immunotherapy has been developed to redirect immunity against tumors.CAR-T cell therapy,have been actively explored for targeting tumor.Challenges remains with CAR-T cell because of its lengthy procedure and high cost,which limits its application.We herein report an alternative approach for tumor therapy via metabolically incorporated antigen to tumor cell surface.Cell surface sialic acids mediates immunological recognition.We propose a small molecular probe based immunotherapy via covalent incorporation of non-self immunogen into tumor glycocalyx with sialic acids derivative to triggerredirect immunity against tumors.This dissertation is consists of three chapters summarized as follows:Chapter 1,include a general introduction of the historical background of cancer immunotherapy,current studies of chimeric antibody receptor T cell immunotherapy,an introduction of properties and functions of sialic acid and the research progress of tumor associzted antigen was introduced.Chapter 2,described the use of DNPSia,a non-self immunogen tagged monosaccharide,to trigger immunity against tumors in mice.DNPSia is preferentially taken up by tumors and then metabolically incorporated into the cell surface,enabling marked suppression of pulmonary metastasis of DNPSia-bearing B16F10 melanoma cells and suppression of subcutaneous tumor formation by intravenously injected DNPSia in DNPKLH-imnunized mice.Given the high levels of natural anti-DNP antibodies in humans,DNPSia on the outmost glycocalyx is well-positioned to recruit pre-existing antibodies and might offer a simplified immunotherapy in humans without recourse to preimmunization,has a broad application prospects.Chapter 3,described the efforts to coyalently introduce the rhamnose to cell surface via sialic acid metabolism to redirect immunity against tumors.Specifically,RhaSia was designed and synthesized,and its distribution in tumor cells was observed in vitro,the results was analyzed.In summary,given the high levels of natural antibodies in humans and ubiquitous sialylation across many cancers,this work offers a simplified route to redirect immunity against diverse tumors without recourse to preimmunization via a metabolically incorporated non-self antigen to tumor cell surface.