NK cells mean Natural Killer cells. They are part of the innate immune system. They are known primarily for their ability to recognize and kill tumor cells, cells infected by viruses and bacteria, or dying by apoptosis. Although evidence about their antitumoral capacity, how this activity occurred remained unknown.
The Stem cell transplant and cell immunotherapy group of the Josep Carreras Leukemia Research Institute (IJC), in a joint investigation with the Hospital Clinic Foundation of Barcelona, has recently revealed this mystery in myeloma, described in a scientific article.
A: Co-localisation of CD138 in myeloma cells with histone H2AZ. In the image above myeloma cells are shown alone, and in the image below after the addition of histone H2AZ. B: Anti-myeloma activity of histone H2AZ. The bioluminescent signal emitted by myeloma cells is shown in mice that received tumor cells alone, or were treated with histone H2AZ. C. Immunoregulatory activity of histones on T lymphocytes released by NK cells. Myeloma cells were co-cultured with NK cells derived from umbilical cord blood (CB-NK) and the released supernatant containing histones (SIPs siRNA) ctrl). On the other hand, NK cells which histone expression (SIPs siRNA Histones) had been decreased were used, D. The supernatants were added to T lymphocytes co-cultured with MM cells, showing that the histones in this supernatant increase the formation of Clusters between T lymphocytes and myeloma cells, and the anti-myeloma activity of T lymphocytes. Image credit: Beatriz Martín
Before this investigation, in another article published by the same group, they observed that when NKs came into contact with myeloma tumor cells, NKs adhered to them, and there was a transfer of molecules between both cells. Still, they did not know which exactly were those molecules. In the most recent investigation, they discovered that NKs, after contact with myeloma cells, released histones that bind to myeloma cells through CD138 receptors, which are much more numerous in myeloma cells than in other cell types.
Histones are proteins whose primary function is to associate with DNA to pack it in the cell nucleus, but also have antitumor capacity inside the tumoral cells.
Once linked to CD138, histones penetrate myeloma cells. What researchers have discovered is that they promote aggregation between tumor cells to form clusters, which expose them to a more effective immune attack, while they also improve the call of T lymphocytes, increasing the antitumor activity.
This study demonstrates that when an NK cell meets a myeloma cell, the NK cell binds to the CD138 receptor on the myeloma cell surface and transfers histones. Histones move inside the cell, exert their antitumor activity, promote myeloma cells agglutination in clusters, and attract T lymphocytes to the battlefield — a whole military strategy of the immune system.
This research has been funded by the Josep Carreras Foundation, the Clínic Foundation, CERCA Generalitat de Catalunya and the PI01043 project of the Carlos III Health Institute.
Story source: B. Martín-Antonio, G. Suñe, A. Najjar, L. Perez-Amill, A. Antoñana-Vildosola, M. Castella, S. León, M. Velasco-de Andrés, F. Lozano4,6,7, E. Lozano, C. Bueno, J. M. Estanyol, C. Muñoz-Pinedo, S. N. Robinson and A. Urbano-Ispizua. Extracellular NK histones promote immune cell anti-tumor activity by inducing cell clusters through binding to CD138 receptor. Oct 2019. Journal for Immunotherapy of Cancer.