NK cells in brain tumors: From biology to treatment

Natural killer cells are key elements of the innate immune defense system. Its inherent therapeutic advantages include not requiring prior sensitization to target transformed malignant cells, decreased incidence of graft-versus-host disease, and activation via antibody-dependent cell-mediated cytotoxicity. These biological properties of NK cells have favored its exploration and use in adoptive immunotherapy for brain tumors over recent years. Even though the last few years have witnessed an explosion of biological data, targeted therapy including adoptive cellular therapy for highly aggressive brain tumors such as GBM and DIPG, survival outcome continues to remain dismal. This is being increasingly attributed to an immunosuppressive cross talk between tumors and the immune microenvironment, which interferes with NK cell tumor homing, activation, and cytotoxicity. Improved understanding of biological mechanisms underlying therapeutic failure and resistance to NK cell therapy will allow development of combination therapy that will circumvent or overcome immunosuppression and improve outcomes in patients with brain tumors. Genetic engineering of NK cells is also being considered to improve targeting of brain tumors. These strategies could involve either NK cells alone or in combination with other immune strategies, to address multiple immunosuppressive mechanisms that have contributed to therapeutic failure of immunotherapy against brain tumors.