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NUS Graduate School for Integrative Sciences and Engineering Research Project Write-up Title of Project : The regulation of γδT17 cells in the tumor microenvironment Name of Supervisor : Liu Haiyan Contact Details: [email protected] Short Description Tumor-promoting inflammation has long been noticed by the progression of chronic inflammation to cancer. However, many questions arise as to which subsets of immune cells directly or indirectly promote malignancy, which of these can be reprogrammed on their functional plasticity to instead combat cancer. Our recent study demonstrated the suppressive role of γδT17 cells (γδT cells producing IL-17A) on the anti-tumor immune response and revealed a novel mechanism involving crosstalk between γδT cells, MDSCs and tumor cells through IL-17A production in the tumor microenvironment. However, the mechanism of γδT17 cell differentiation and regulation during tumor development is still unknown. On the other hand, γδT cells have long been harnessed in anti-tumor immunotherapy. γδT17 cells were also reported to promote anti-tumor immune response during chemotherapy and radiotherapy. We hypothesize that γδT17 cells could exert different immune regulatory roles in different tumor microenvironment. Their immune-suppressive function could be reversed by modulating key elements in the tumor microenvironment. Objective of the project: to define the key molecules and cell subsets that induce γδT17 cell differentiation during tumor development; to investigate in a murine tumor model how γδT17 cells are differentially regulated in different tumor microenvironment; to design immunotherapeutic strategies to modulate γδT17 cell functions to combat cancer. NUS Graduate School for Integrative Sciences and Engineering Research Project Write-up Title of Project : γδT cell adoptive cancer immunotherapy Name of Supervisor : Liu Haiyan Contact Details: [email protected] Short Description Immunotherapy has been one of the major breakthroughs in cancer therapy in recent years. Adoptive cell transfer therapy harnesses the power of the immune system by stimulating and expanding immune cells to combat cancer. The application of tumor-specific αβT cell-based therapy may be hindered by limited tumor antigens. Abundant IFNγ or IL-17 production, MHC-independent cytotoxicity against a broad spectrum of tumors make γδT cells promising candidates for cellular immunotherapy. However, the tools for expanding γδT cells are very limited. Phosphoantigen stimulation can only expand human Vγ9Vδ2 T cells and may not generate the robust effector cells. Anti-T cell receptor (TCR) γδ antibody-expanded human γδ T cells exhibit higher levels of cytotoxicity and anti-tumor activity. Therefore, antibodybased expansion could be more suitable for cancer immunotherapy. Antibody-based expansion is also the only available method for expanding murine γδT cells. Moreover, antibodies specific for Vγ or Vδ chains can expand specific subsets of γδT cells, which have been shown to have distinct functions in certain tumor types. Despite the essential capability of the anti-TCRγδ antibodies as the cell-based therapeutic as well as research tools, there are very few clones of them that are available commercially. Therefore, generation of monoclonal antibodies to expand γδT cells ex vivo is critical for γδT cell research and cellular therapy. Cytokines can greatly influence the differentiation and function of the expanded γδT cells. Antibodybased expansion of γδT cells can also be optimized for their in vivo function using different culture systems of cytokine combinations and evaluated in humanized or murine animal models. We will pursue the following aims to generate efficient antibody-based expansion system for γδT subsets and evaluate their anti-tumor activities in vitro and in vivo. Aim 1: Generate monoclonal antibodies specific to murine Vγ and human Vδ chains that can expand human and murine γδT cell subsets ex vivo. Aim2: Determine the optimal expansion conditions for γδT cell subsets. Aim3: Compare anti-tumor capacities of different γδT cell subsets to provide better solutions for γδT cell-based cancer therapy. The availability of some of the murine anti-Vγ antibodies would make it possible to study the anti-tumor activity of some unique subsets of γδT cells. Human γδT cells expanded with monoclonal antibodies have been shown to possess potent anti-tumor activity. Different γδT cell subsets expanded with antibodies will be examined and compared for their efficacies in anti-tumor immunotherapy.