Natural killer cells in the brain tumor microenvironment: Defining a new era in neuro-oncology.

Abstract

Malignant brain tumors cultivate a variety of mechanisms to escape local and systemic immunity. Current treatments are restricted to neurosurgical procedures, chemotherapy, and radiotherapy.[34] The major limitation to effective therapeutic strategies lies in the impermissibility of the blood–brain barrier, which blocks the access of targeted drugs into tumor sites.[15] For long, it was believed that the lack of lymphatic drainage and antigen-presenting cells protects brain tumors from immunity; however, preclinical and translational studies in the past decade changed the perception on the role of immune cells in brain tumors.[12,32,37] Brain tumor cells are equipped with the ability of secreting numerous chemokines, cytokines, and growth factors that stimulate the infiltration of various neural cells and a range of immune cells into the tumor. Altogether, these cells create a special niche called the tumor microenvironment, which is crucial for cancer proliferation, spread, and response to treatment. The tumor microenvironment has the ability of reprogramming attacking immune cells through local release of cytokines and chemokines,[17] which leads to protumor inflammatory or anti-inflammatory responses. Similar to other cancers, the brain tumor microenvironment has evolved multiple ways to inhibit the antitumor activity of immune cells.[29] Glioma research has shown that a strong link exists between the immune system response and disease progression.[18,31,35] Natural killer (NK) cells are large granular lymphocytes that play an important role in antitumor immunity. On activation, NK cells induce target cell apoptosis through contact-dependent cytotoxicity primarily mediated by perforin and granzyme B[7,9,25] and secretion of pro-inflammatory cytokines such as tumor necrosis factor-α and interferon-γ.[6,27,36] In brain tumors, NK cells have proven to be effective in in vitro[2,4,8] and in vivo[1,16,30] settings. They can recognize and kill human glioblastoma cells that exhibit stem cell-like properties.[4,8] Therefore, in this paper, we explore the role of NK cells in the brain tumor microenvironment and discuss the challenges facing possible therapeutic regimens using NK cells against brain tumors.