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Abstract
The γδ T cells are unconventional lymphocytes that function in both innate and adaptive immune responses against various intracellular and infectious stresses. The γδ T cells can be exploited as cancer-killing effector cells since γδ TCRs recognize MHC-like molecules and growth factor receptors that are upregulated in cancer cells, and γδ T cells can differentiate into cytotoxic effector cells. However, γδ 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 γδ T cells are regulated and whether distinct γδ T cell subsets have different functions. Human γδ T cells are classified into Vδ2 and non-Vδ2 γδ T cells. The majority of Vδ2 γδ T cells are Vγ9δ2 T cells that recognize pyrophosphorylated isoprenoids generated by the dysregulated mevalonate pathway. In contrast, Vδ1 T cells expand from initially diverse TCR repertoire in patients with infectious diseases and cancers. The ligands of Vδ1 T cells are diverse and include the growth factor receptors such as endothelial protein C receptor. Both Vδ1 and Vδ2 γδ 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 γδ T cells. Here, we summarize recent progress regarding cancer immunology of human γδ 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.
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Figure 1.
Differential recruitment of Vδ1 and Vγ9δ2 γδ T cells into the tumor tissue. In blood, Vγ9δ2 γδ T cells are predominant over Vδ2 γδ T cells in healthy individuals. Most of the Vγ9δ2 γδ T cells have canonical TCRs responding to prenyl pyrophosphates that are elevated in cancer cells and are recruited into the tumor via chemokine receptors. In contrast, some clonotypes of Vδ1 γδ T cells are selected from a diverse Vδ1 TCR repertoire. Specific Vδ1 γδ T cells migrate into the tumor tissues, expand, and kill cancer cells. The tissue-resident Vδ1 γδ T cells may respond to the tissue stress and proliferate to kill cancer cells.
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