From natural to eximious : harnessing the power of natural killer cells against solid tumors

Abstract: Cancer heterogeneity, which enables clonal survival and treatment resistance, is shaped by active immune responses. Unchallenged results from clinical trials show the power of stimulating our immune system to attack tumor cells. Engineered T cells and checkpoint blockade are at the forefront of current immunotherapy strategies. Whereas our immune system includes a diverse range of effector cells, which could directly or indirectly kill the target cells, and these immune cells must organize in a synergistic way to overcome multiple immune-evasion mechanisms and achieve complete tumor eradication. An essential type of effector cell is natural killer (NK) cell. These are cytotoxic innate lymphocytes identified by their splendid capacity to kill virus-infected, stressed or transformed cells. Ex vivo expanded NK cells used for hematological malignancies showed promising results, associated with in vivo NK cells expansion after infusion. However, due to the limited growth factors in the tumor microenvironment (TME), infused NK cells undergo changes in their phenotype and ability to survive. The type I cytokine family members IL-2 and IL-15 play a pivotal role to maintain homeostasis of the innate and adaptive immunity. Endogenous levels of IL-15 have been linked with sustained persistence of infused NK cells. Thus, the secret for NK cell resistance in the TME could be uncovered by investigating IL-15 primed NK cells under various forms of immunosuppression. In study I, we found that IL-15 primed NK cells acquire resistance against prostaglandin E2 (PGE2) mediated suppression by upregulation of phosphodiesterase 4A (PDE4A) in CD25+CD54+ NK cells. These CD25+CD54+ NK cells showed superior killing capacity under the suppression of PGE2 in vitro (2D and 3D culture) and in vivo (zebrafish model) experiments. In study II, we demonstrated that upregulated mTOR pathway primed by IL-15 lead to increased thiol density which protected not only NK cells but other lymphocytes against ROS in tumor microenvironment. In study III, we showed that upregulation of the IL-2α receptor (CD25) in NK cells enables an immunometabolic competition of IL-2 in the TME between Treg and NK cells. In summary, this thesis provides mechanistic insights for tumor-NK cell interaction and elucidates the potential therapeutic approach for harvesting "eximious" NK cells against solid tumors.