Cytokine therapy enhances the activity of natural killer (NK) cells against tumors that lack the cell surface protein known as MHC class I, according to new research published in the Journal of Clinical Investigation (2014; doi:10.1172/JCI74337).
NK cells are sentinels within the immune system that rapidly respond to and kill diseased cells. NK cells typically target and eliminate cells lacking the surface protein MHC class I. However, many tumor cells lack this protein yet evade NK cell surveillance and killing, though how this evasion occurs is unknown.
Cytokines are known to be powerful modulators of the immune system, and many of the cytokines used in clinical trials activate NK cells, whether directly or indirectly.
Using mouse models, David Raulet, PhD, and colleagues at the University of California Berkeley determined that tumors lacking MHC class I inactivate NK cells. When cytokines were absent, the NK cells were anergic, or did not have an immune response, to tumors deficient in MHC class I. Mixed tumors composed of MHC class I positive and MHC class I negative cells also caused NK cell to become nonresponsive, or anergic.
Importantly, treatment of mice bearing MHC class I-deficient tumors with the cytokines IL-12 and IL-18 or with the H9 superkine restored NK cell activity, reduced tumor size, and increased survival. The cytokine treatment reversed the anergy of the NK cells within the tumors, meaning that an immune response occurred.
The results of this study support further investigation into the use of cytokine therapy for patients with tumors lacking MHC class I. The authors wrote that such cytokine therapies would be optimized by stratification of patients.
Further, the authors stated that their results indicate that cytokine therapies “may be highly beneficial in the context of therapies to enhance NK cell functions in cancer patients.”