NKG2A Immune Checkpoint in Vδ2 T Cells: Emerging Application in Cancer Immunotherapy

Abstract

Immune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). This successful immunotherapy has led to a more complete view of cancer that now considers not only the cancer cells to be targeted and destroyed but also the immune environment of the cancer cells. Current challenges associated with the enhancement of ICI effects are increasing the fraction of responding patients through personalized combinations of multiple ICIs and overcoming acquired resistance. This requires a complete overview of the anti-tumor immune response, which depends on a complex interplay between innate and adaptive immune cells with the tumor microenvironment. The NKG2A was revealed to be a key immune checkpoint for both Natural Killer (NK) cells and T cells. Monalizumab, a humanized anti-NKG2A antibody, enhances NK cell activity against various tumor cells and rescues CD8 αβ T cell function in combination with PD-1/PD-L1 blockade. In this review, we discuss the potential for targeting NKG2A expressed on tumor-sensing human γδ T cells, mostly on the specific Vδ2 T cell subset, in order to emphasize its importance and potential in the development of new ICI-based therapeutic approaches.

Controversial role of γδ T cells in colorectal cancer

“…The second approach stimulates and amplifies γδ T cells in vivo through the systemic administration of PAG or nitrogen-containing bisphosphonates [83]. The clinical applications of γδ T cells started with the attempt to directly amplify in vivo autologous Vδ2 T cells and were based on their ability to penetrate solid tumors and readily expand [121]. Most early studies attempted to activate Vδ2T cells by direct application of nitrogen-containing bisphosphonates or synthetic PAG and low doses of IL-2.…”

Non-Classical HLA Class 1b and Hepatocellular Carcinoma

“…It is thought that a sizable number of NKG2A+ Vδ2 T cells may improve overall survival in HCC when the level of HLA-E is reduced, or similar to, normal tissue. Based on these studies and the evidence that educated NKG2A+ Vδ2 T cells are more responsive, the prognosis of HCC may be improved by the development of therapies based on NKG2A-HLA-E immune checkpoint inhibition [ 191 , 192 ]. Most studies are ongoing, but currently only in preclinical models and in different cancer types, e.g., [ 193 , 194 , 195 , 196 ].…”

Identification of Tissue-Resident Natural Killer and T Lymphocytes with Anti-Tumor Properties in Ascites of Ovarian Cancer Patients

“…Among the inhibitory receptors, the dimer composed of CD94 and NKG2A (hereafter referred to as NKG2A) is expressed on about half of the peripheral blood NK cells and binds to the non-classical MHC class I molecule, HLA-E. Variable inhibitory killer-cell immunoglobin-like receptors (KIR) are expressed to various extents on subsets of NK cells and bind to classical MHC class I molecules HLA-A, -B or -C. NKG2A can regulate both adaptive and innate immunity as it is expressed not only on NK cells, but also on conventional CD8 + T lymphocytes [ 11 ], as well as unconventional T cell populations, such as NKT cells [ 12 ] and γδ T cells [ 13 , 14 ].…”