Anti-tumor and pro-tumor interactions of human NK cells in cancerWong, Jeffrey L. (2013) Anti-tumor and pro-tumor interactions of human NK cells in cancer. Doctoral Dissertation, University of Pittsburgh. (Unpublished)
AbstractWhile natural killer (NK) cells have been classically understood as innate cytotoxic effector cells, a new paradigm has emerged involving NK cells as key immunomodulators in the development of both innate and adaptive immune responses. In particular, NK cells can critically shape the character of anti-cancer immunity through their engagement with dendritic cells (DCs). Thus, understanding the interactions of NK cells with DCs, as well as other cell types in the human tumor environment, is essential to understanding endogenous anti-tumor immune responses and developing effective cancer immunotherapies. In this work, we show that human NK cells can perform distinct 'effector' and 'helper' activities, which can be uniquely driven by distinct cytokine activation. While IL-2-activated 'effector' NK cells efficiently kill tumor cells and both immature and mature DCs, IL-18-activated 'helper' NK cells instead uniquely potentiate anti-tumor immune responses through DC activation and the enhancement of DC-induced type-1 immunity. These IL-18-activated helper NK cells further recruit DCs, facilitating productive NK-DC interaction, and subsequently collaborate with DCs in promoting chemokine environments conducive to naïve T cell priming in the lymph nodes as well as effector T cell infiltration into peripheral tumor sites. However, our studies also indicate that, in addition to their desirable anti-tumor type-1-polarizing interactions with DCs, such IL-18-activated NK cells may also have undesirable pro-tumor effects through their IFNg- and TNFa-dependent hyper-activation of myeloid-derived suppressor cells (MDSCs), a critical cell population present in most cancers that play a major role in tumor-associated immune suppression and the potential modulation of Th17 immunity. Using MDSCs isolated directly from the malignant ascites of patients with late-stage ovarian cancer, we implicate autocrine COX2/PGE2 feedback as essential in NK cell-mediated MDSC hyper-activation, highlighting the possibility for therapeutic COX2/PGE2 axis inhibition in reversing the pro-tumor NK cell-mediated up-regulation of MDSC activity, while preserving or enhancing the anti-tumor NK cell-mediated activation of DCs. Overall, these studies help to better understand the interactions between NK cells, DCs, and MDSCs in cancer immunity, and identify new targets for the therapeutic manipulation of anti- and pro-tumor NK cell activities for the improvement of cancer therapy. Share
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