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Gammadelta T-cells (γδT cells) were originally discovered as a result of a search for the significance of a rearranging T cell receptor (TCR) gene, γ, which did not appear to be expressed at the protein level in CD4+ or CD8+ αβTCR+ T cells. In one of two first papers that unveiled these cells, it was noted ...

Gammadelta T-cells (γδT cells) were originally discovered as a result of a search for the significance of a rearranging T cell receptor (TCR) gene, γ, which did not appear to be expressed at the protein level in CD4+ or CD8+ αβTCR+ T cells. In one of two first papers that unveiled these cells, it was noted that triggering the γδTCR with an antibody to CD3 induced potent in vitro cytotoxicity against leukemic cells. Since then, accumulating studies have demonstrated that γδT cells play a critical role in cancer prevention, control and progression, by employing unique as well as overlapping immunological principles relative to αβTCR+ T cells and NK cells. Unique features include recognition by Vγ9Vδ2+ γδTCR of phosphoantigens that are increased in cancer, and of tumor-associated stress molecules such as UL16 binding protein by NKG2D. In addition, γδT cells can present tumor antigens to αβT cells to enhance their anti-tumoral activity.

Beyond these functions, γδT cells could prove to be highly beneficial in cancer treatment regimens because of their lack of alloreactivity, which suggests that “off the shelf” allogeneic γδT cells could be used for therapy. In support of this emerging concept, it has already been shown that resistant leukemia can be successfully treated with haploidentical bone marrow transplants depleted of αβ and enriched in γδT cells that were activated in vivo using zoledrone. In addition, an objective regression of metastatic cholangio-carcinoma following infusions of allogeneic Vγ9Vδ2+ γδT cells was reported. Furthermore, the more variable Vδ1 subsets also display cytotoxic effects against leukemic and other cancer cells. Importantly, although some features, notably IL-17 production by certain γδ T cells have been implicated in driving cancer progression, a survey correlating survival from 39 different types of human cancer with transcriptional signatures of immune cells, identified those associated with γδT cells as the most significant positive prognostic indicator.

However, despite sporadic reports of beneficial effects of γδ autologous transfusions in cancer patients, the nature of the so far reported clinical trials (i.e. Phase I primarily, using autologous preparations), the lack of uniformity in the cellular preparations and of the number of cells transfused, as well as the small number and diversity of patients studied, have not allowed for definitive conclusions on the utility of γδT cell-mediated therapy so far. In an effort to overcome these limitations, and building on the novel insights from recent research (most notably the role of butyrophilins in recognition of phosphoantigens by Vγ9Vδ2+ γδT cells, improved methods of ex vivo amplification, as well as development of CAR technologies) there is renewed interest in bringing γδT cells to the cancer clinic. This has been reinforced by the exciting results of immune checkpoint inhibition and CAR-T cell therapy for various cancers, along with the recognition that these would not be sufficient to vanquish cancer in a high proportion of patients. Indeed, the recent progress in the understanding of the complex biology of γδT cells is positioning both Vγ9Vδ2+ and Vδ1 γδT cells on the verge of becoming rational therapeutic strategies for cancer.

In this Research Topic, we welcome the submission of Original Research and Methods articles, as well as Clinical Trials relating to the role of γδ T cells in cancer, with an emphasis on immunotherapeutic applications. Contributions that cover, but are not limited to, the following topics are welcome:

1. γδT cell recognition of transformed malignant cells;
2. γδT cell killing mechanisms of transformed cells;
3. Mechanisms of γδ T cell migration, distribution and interaction with the tumor microenvironment;
4. Pre-clinical proof-of-concept studies in animal models of cancer;
5. Clinical studies involving use of γδ T cells in cancer immunotherapy.

Topic Editor Prof. Ilan Bank is Chief Scientific Officer of GammaCell Bio-Technologies Ltd. Topic Editor Prof. Jurgen Kuball is co-founder and scientific advisor of GADETA. Topic Editor Prof. Bruno Silva-Santos is co-founder of Lymphact S.A., a company now owned by GammaDelta Therapeutics. All other Topic Editors declare no competing interests with regards to the Research Topic subject.

We acknowledge the initiation and support of this Research Topic by the International Union of Immunological Societies (IUIS). Dr. Dieter Kabelitz currently serves as the chairman for the IUIS Education Committee.

Keywords: Society affiliation RT

Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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