γδ T cells in cancer immunotherapy

The largest subset of human γδ T cells is the Vγ2 (alternate Vγ9) Vδ2 subset, comprising 2% to 5% of peripheral blood T cells. These Vγ2Vδ2 T cells uniformly recognize nonpeptide alkylamine, nitrogen-containing bisphosphonate, and organophosphate antigens in a T cell receptor (TCR)—dependent fashion. Such recognition enhances γδ T cell—mediated cytotoxicity, and secretion of IFN-γ and TNF-α, which are important antitumor effector mechanisms (Morita et al, Springer Sem Immunopath. 2000;22:191-217).

Mouse models provide strong evidence for γδ T cell—mediated resistance to tumors and infection. In humans, certain lymphoma and myeloma cells display cell-surface antigens that are recognized in a Vγ2Vδ2 TCR-dependent manner. Others display nonclassical major histocompatibility complex (MHC) class I—related proteins such as MHC class I—related chain A (MICA) and UL16 binding proteins (ULBPs) that can be recognized by NKG2D receptors on activated γδ T cells. Cells from common cancers metastatic to bone, such as those from breast cancer and prostate cancer, can be exposed to large concentrations of bone-avid nitrogen-containing bisphosphonates, such as pamidronate and risedronate. Such exposure may kill these cells directly, in several days, but γδ T cells can kill these sensitized cells in a matter of minutes. Thus, bisphosphonates can at once activate γδ T cells and sensitize tumor cells for elimination by γδ T cells (Das et al, Blood. 2001;98:1616-1618). Treatment of multiple myeloma with pamidronate has increased survival and decreased the incidence of metastatic lesions and pathologic fractures (Berenson et al, J Clin Oncol. 1998;16:593-602).

In this issue, Wilhelm and colleagues (page 200) report successful treatment of refractory lymphoma and myeloma with pamidronate and interleukin 2 (IL-2). Importantly, objective clinical responses correlated with proliferation of γδ T cells in vivo, strongly suggesting a role for γδ T cells in mediating the response. As more potent γδ T-cell antigens are coupled with treatments earlier in disease, we can soon expect even better results. These data represent an important initial step in manipulating γδ T cells in vivo to treat tumors and, perhaps, to treat or prevent infections that accompany them.