Heterogeneity of Human γδd T Cells and Their Role in Cancer Immunity

The gamma delta T cells are unconventional lymphocytes that function in both innate and adaptive immune responses against various intracellular and infectious stresses. The gamma delta T cells can be exploited as cancer-killing effector cells since.d TCRs recognize MHC-like molecules and growth factor receptors that are upregulated in cancer cells, and gamma delta T cells can differentiate into cytotoxic effector cells. However, gamma delta T cells may also promote tumor progression by secreting IL-17 or other cytokines. Therefore, it is essential to understand how the differentiation and homeostasis of gamma delta T cells are regulated and whether distinct gamma delta T cell subsets have different functions. Human gamma delta T cells are classified into V delta 2 and non-V delta 2 gamma delta T cells. The majority of Vd2 gamma delta T cells are V gamma 9 delta 2 T cells that recognize pyrophosphorylated isoprenoids generated by the dysregulated mevalonate pathway. In contrast, V delta 1 T cells expand from initially diverse TCR repertoire in patients with infectious diseases and cancers. The ligands of V delta 1 T cells are diverse and include the growth factor receptors such as endothelial protein C receptor. Both V delta 1 and V delta 2 gamma delta T cells are implicated to have immunotherapeutic potentials for cancers, but the detailed elucidation of the distinct characteristics of 2 populations will be required to enhance the immunotherapeutic potential of gamma delta T cells. Here, we summarize recent progress regarding cancer immunology of human gamma delta T cells, including their development, heterogeneity, and plasticity, the putative mechanisms underlying ligand recognition and activation, and their dual effects on tumor progression in the tumor microenvironment.