Trends in Immunology

Trends in Immunology

Volume 37, Issue 12, December 2016, Pages 877-888
Journal home page for Trends in Immunology

Review
Harnessing NK Cell Memory for Cancer Immunotherapy

https://doi.org/10.1016/j.it.2016.09.005Get rights and content

Trends

Over the past decade it has been recognized that human and murine natural killer (NK) cells have properties of immunologic memory, with long-lasting enhanced functionality following stimulation with antigens, cytomegalovirus, or cytokines.

NK cell immunotherapy strategies for the treatment of cancer are currently under clinical investigation and there is now evidence that some types of memory NK cells have enhanced antitumor properties.

A better understanding of the mechanisms of NK cell memory formation and the functional properties of different types of memory cells is essential for harnessing the antitumor properties of these lymphocytes for the treatment of human disease.

Due to their ability to kill cancer cells and produce proinflammatory cytokines, natural killer (NK) cells have long been of clinical interest for their antitumor properties. The recent discovery of NK cell memory demonstrates that NK cell functions, and potentially antitumor responses, can be enhanced long term. Following nonspecific activation with the cytokines IL-12, IL-15, and IL-18 or in response to antigens or cytomegalovirus (CMV), human and mouse NK cells exhibit stable, enhanced functional responses with phenotypic and molecular changes. Here we review mechanisms driving the differentiation of NK cell memory-like properties, evidence for antitumor activity, and the challenges and opportunities in harnessing memory-like NK cells for cancer immunotherapy.

Section snippets

Natural Killer Cells and Cancer Immunotherapy

NK cells are innate immune lymphocytes first identified in the 1970s based on their functional ability to kill tumor cells without MHC restriction or prior sensitization [1]. NK cells constitutively express germline-encoded inhibitory receptors that recognize MHC class I molecules and provide inhibitory signals for self. These inhibitory signals are important for tolerance and also shape the responsiveness of NK cells during their development, a process termed education. Additionally, NK cells

Memory NK Cell Differentiation

NK cells can adapt their behavior based on prior activation, with enhanced functionality after a single activation event [9]. Enhanced NK cell function has been observed in response to antigen-specific stimulation and antigen-independent cytokine activation. Such NK cells have been referred to as ‘memory’, ‘adaptive’, or ‘memory-like’ depending on the context in which the NK cells were activated. Three major differentiation pathways for NK cell memory responses have been identified to date:

Antitumor Responses of Memory NK Cells

Memory NK cell antitumor responses have been best studied in the context of HCMV adaptive NK cells and cytokine-induced memory-like NK cells. Here we focus on the potential of these types of memory NK cells for cancer immunotherapy, including key differences between mouse and human systems (Table 1).

Improving Tumor Cell Recognition and Triggering of Memory NK Cells

Multiple studies have demonstrated that HCMV epigenetically programs adaptive NK cells for enhanced FcγRIIIa-triggered cytokine responses 36, 38, 40. Similarly, cytokine-induced memory-like NK cells exhibit enhanced responsiveness when triggered via FcγRIIIa [53] and show evidence of epigenetic alterations in the Ifng gene in the mouse system [51], identifying a potential common activating receptor strategy to direct human memory NK cells against cancer. Therapeutic monoclonal antibodies

Concluding Remarks

The emergence of the concept of long-lasting NK cell memory responses has led to investigation of their antitumor properties. There are many remaining questions regarding the biology of NK cell memory and its applicability to the treatment of cancer (see Outstanding Questions). Studies of mouse and human cytokine-driven memory-like NK cells suggest that they have enhanced antitumor responses and led to the first clinical trial administering these cells to patients with AML. HCMV-adaptive NK

Acknowledgments

Work in the Fehniger laboratory is supported by R01 AI102924, Leukemia SPORE P50 CA171963, the Siteman Cancer Center P30 CA91842, Gabrielle's Angel Foundation for Cancer Research, and the Leukemia and Lymphoma Society. Work in the Cooper laboratory is supported by the Rheumatology Research Foundation.

What forms of NK cell memory are most relevant for health and disease in humans? Do cytokine-induced memory-like NK cells arise in humans under physiologic conditions and how can they be

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