Background Natural Killer (NK) cells are innate immune cells able to reject hematological malignancies and correlate with better prognosis in solid tumors. However, conventional NK (cNK) cell anti-tumor activity is limited by the immune suppressive tumor microenvironment (TME). The subset of NK cells, adaptive NK (aNK) cells have immunological memory and accumulate in cytomegalovirus (CMV) infected individuals.1 These aNK cells can resist immune suppression of the TME.2 Glioblastoma (GBM) is the most aggressive brain tumor that has a very poor dismal prognosis and immunosuppressive TME.3
Methods We develop an artificial 3D model of GBM TME, using U251 tumor cells, myeloid derived suppressor cells (MDSC), and NK cells, to analyze the tumor infiltration and killing by NK cells that have developed memory against autologous tumor antigens presented by dendritic cells (DCs), using the live imaging analyzer Incucyte.
Results Our data suggest that aNK cells recognize GBM antigens and we demonstrate that NK cells can infiltrate and kill tumor cells (figure 1), especially when previously primed by antigen loaded DCs. Furthermore, using a flow cytometry-based analysis called Metflow we have discovered that aNK cells have a different metabolic profile than cNK cells. While cNK cells were dysfunctional in the TME when inhibiting glycolysis, aNK cells were still activated relaying on alternative metabolic pathways, such as the TCA cycle (figure 2).
Conclusions Our data suggest that aNK cells have a higher metabolic plasticity and resistance to TME, making them a great target for immunotherapy against GBM tumors.
Sun JC, Beilke JN, Lanier LL. Immune memory redefined: characterizing the longevity of natural killer cells. Immunol Rev 2010;236:83–94.
Sarhan D, et al. Adaptive NK Cells with Low TIGIT Expression Are Inherently Resistant to Myeloid-Derived Suppressor Cells. Cancer Res 2016;76:5696–5706.
Grech N, Dalli T, Mizzi S, Meilak L, Calleja N, Zrinzo A. Rising Incidence of Glioblastoma Multiforme in a Well-Defined Population. Cureus. 2020 May 19;12(5):e8195. doi: 10.7759/cureus.8195. PMID: 32572354; PMCID: PMC7302718.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.