Using γδ T cells for Cancer Adoptive Immunotherapy

γδ T cells are small subset of blood T lymphocytes; consist 1-5% of blood T lymphocytes. As their name indicates; γδ T cells express γδT cell receptors. Unlike αδ T cells, γδ T cells cannot recognize peptide Antigens. Instead, γδ T cells recognize phosphoantigens such as Isoperenyal pyrophosphate (IPP) by their TCRs in MHC- independent manner. Tumor cells and some pathogenic microbes can produce IPP through metabolic pathway called "Mevalonate pathway" and activate γδ T cells. Activated γδ T cells can function as a part of innate and adoptive immune response. In fact, γδ T cells bridge the innate and adoptive immune responses. There are several subsets of γδ T cells can be found in different anatomical locations, but Vγ2Vδ2 is the most common subset of human blood γδ T cells.

Activated γδ T cells consider a promising and strong candidate for cancer immunotherapy because they have shown such a strong cytotoxicity against some types of cancers. Many researches are being done focusing on anti-tumor aspect of γδ T cells. Currently, Zoledronate, which is an anti-tumor drug, is being used to stimulate the expansion and proliferation of γδ T cells by blocking the Mevolanate pathway down stream IPP and cause IPP accumulation. There are some clinical trials showed a successful treatment of certain types of tumor by using ex-vivo expanded γδ T cells. However, the current approach that is being used to expand γδ cells, is not optimal and there are several limitations and caveats came out during those clinical trials. Some of those limitations that need to be solved are the cytotoxicity of Zoledronate on γδ T cells themselves, and the differences in patients' response to the γδ immunotherapy; it turned out that some patients didn't respond to γδ adoptive immunotherapy while others did.

My research is focusing on optimizing the adoptive immunotherapyf γδ T cells by find a way to maximize the γδ expansion and minimize the Zoledronate cytotoxicity. Also, we are working on finding a way to predict the patients who can be good candidates for γδ Immunotherapy.

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Nada MH, Wang H, Workalemahu G, Tanaka Y, Morita CT. Enhancing adoptive cancer immunotherapy with Vγ2Vδ2 T cells through pulse zoledronate stimulation. J Immunother Cancer. 2017 Feb 21;5:9. doi: 10.1186/s40425-017-0209-6. PubMed PMID:28239463; PubMed Central PMCID: PMC5319075.

Workalemahua G, Wang H, Puan K-J, Nada MH, Kuzuyama T, Jones BD, Jin C, Morita CT. Metabolic engineering of Salmonella vaccine bacteria to boost human Vγ2Vδ2. T Cell Immunity, J. Immunol. 2014 in press.