Thursday, July 12, 2018

Gamma T Cells and Cancer

Gammadelta T cells (γδ T cells) are T cells that express a unique T-cell receptor (TCR) composed of one γ-chain and one δ-chain. Gammadelta T cells are of low abundance in the body, are found in the gut mucosa, skin, lungs and uterus, and are involved in the initiation and propagation of immune responses. Differentially polarized γδT-cell subsets exhibit functionally diverse responses to tumors, thus potentially leading to antitumor or protumor responses. Generally, human γδT cells are divided into two major structural subsets according to their TCR δ chain usage: Vδ1 and Vδ2 T cells.
γδT cells display cytotoxicity against hematopoietic and solid tumors in an MHC-independent manner. Although their activation mechanisms differ, both Vδ2 and Vδ1 subsets exert potent antitumor effects. One common γδT-cell-mediated killing pattern involves tumor cell recognition via receptor–ligand interactions. TCR is strongly implicated in controlling Vγ9Vδ2 T-cell cytotoxicity via the recognition of phosphoantigens that are overexpressed in tumor cells and mediate tumor cell lysis. NKG2D binds to MICA/B and ULBPs and induces Vγ9Vδ2 T-cell cytotoxicity against hemopoietic and epithelial tumors. Vγ9Vδ2 T cells are induced to produce IFN-γ and kill hepatocellular carcinoma cells via the interaction of DNAM-1 and nectin-like-5. γδT cells also exhibit strong cytotoxicity against myeloma cells via NKp44. Furthermore, CD56+ γδT cells are capable of killing squamous cell carcinoma of the head and neck, a process that is likely to be mediated by the enhanced expression of granzyme B and upregulated degranulation. Similarly to NK cells, γδT cells induce antibody-dependent cell-mediated cytotoxicity (ADCC) effects, thus resulting in the lysis of tumor cells. According to Tokuyama H et al., CD16+ Vγ9Vδ2 T cells recognize monoclonal antibody-coated lymphoma, chronic lymphocytic leukemia (CLL) and breast cancer cells via CD16 and exert ADCC-dependent cytotoxicity. γδT cells mediate ADCC against B-lineage acute lymphoblastic leukemia via CD19 antibodies. In several other studies, γδT cells have also been shown to mediate ADCC effects against tumor cells via CD16 in the presence of therapeutic antitumor monoclonal antibodies. Moreover, γδT cells have antitumor roles by modulating other effector cells. Although γδT cells demonstrate potent antitumor capacity, paradoxically they also exert protumor effects by promoting noncytotoxic inflammation and regulatory functions that subvert cytotoxic antitumor immunity. Intratumoral γδT cell numbers are positively associated with advanced tumor stages and are inversely correlated with breast cancer prognosis.
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