Download The regulation of γδT17 cells in the tumor microenvironment γδT cell adoptive cancer immunotherapy

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.