NKG2A Immune Checkpoint in V2 T Cells: Emerging Application in Cancer Immunotherapy

Boosting effector T cell anti-tumor response remains a challenge, in part owing to the expression of immune checkpoints and their ligands, such as NKG2A and HLA-E. Targeting NKG2A by gene knockout or blocking antibodies improves the cytotoxicity of V delta 2 T cells, a specific subset of human unconventional gamma delta T lymphocytes. Thus, a suitable selection of NKG2A(+) or NKG2A(-) V delta 2 T cells for expansion or engineering could help to narrow the V delta 2 T cell population according to the expression of HLA-E on tumor cells. With this emerging knowledge, approaches to target NKG2A in V delta 2 T cells might be a promising step forward to boosting V delta 2 T cell-based cancer immunotherapies.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 alpha beta 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 gamma delta T cells, mostly on the specific V delta 2 T cell subset, in order to emphasize its importance and potential in the development of new ICI-based therapeutic approaches.