The first report showing a protective effect of cytomegalovirus (CMV) against cancer relapse was published nearly 20 years ago, and this effect has been confirmed in several independent studies, including a large-scale clinical analysis of >2,500 patients with hematologic malignancies. While the protective effect of CMV is presumed to be due to a unique priming of the immune system, the mechanism of this priming is unknown. We are in a new era where the power of the immune response against cancer is just being realized. We have recently discovered oligoclonal expansions of highly differentiated NK cells expressing the activating receptor NKG2C in individuals having past infection with CMV. These NKG2C+ NK cells have an educated phenotype, as they are enriched for the expression of self HLA-C-specific inhibitory KIRs and appear to represent the human equivalent of ?memory? or ?adaptive? NK cells described in CMV-infected mice. Published work by our group has shown that these NKG2C+ NK cells display heightened effector functions, expand in transplant patients in response to reactivation of latent CMV and persist for at least one year post-transplant. They are transplantable from a CMV seropositive donor and expand in a seropositive recipient. We have extensive preliminary data showing that NKG2C is not the only marker for CMV-induced adaptive NK cells. We identified expansions of NK cells selectively lacking the proximal signaling molecules Fc?R1?, EAT-2 and SYK individually or in combination specifically in CMV seropositive blood donors and in transplant recipients that reactivated CMV. These cells are epigenetically primed for enhanced inflammatory cytokine production and survival and are functionally specialized for antibody-dependent cellular cytotoxicity (ADCC) through CD16. We will translate this research into methods to prime NK cells ex vivo or in vivo with potent function and prolonged in vivo survival for clinical use in patients with leukemia. We will test the hypothesis that the expansion of CMV- induced adaptive NK cells is associated with reduced cancer relapse by performing a high-resolution analysis of CMV-induced adaptive NK cells in our well-defined transplant cohorts and correlating this analysis with clinical outcomes. We will also test the hypothesis that STAT3 signaling and CD16 receptor engagement drives the expansion of adaptive NK cells both in vitro and using our bank of clinical samples. Finally, we will use our xenogeneic adoptive NK cell transfer model to test the anti-tumor effect of CMV-induced adaptive NK cells in vivo. The concept of CMV induced adaptive NK cells is new and little is know about these cells in humans. We have already discovered how to identify adaptive NK cell and we have clinical samples collected based on CMV reactivation. We are optimally positioned to definitively answer the question about whether adaptive NK cells can prevent relapse as our preliminary data suggests or treat cancer.

Public Health Relevance

We have recently discovered that highly functional NK cells are found in individuals having past infection with CMV or in bone marrow transplantation patients who reactivate CMV reactivation (a common viral infection in immune compromised patients). We have developed novel ways to identify and study these cells that are primed for enhanced inflammatory cytokine production and are functionally specialized for antibody-dependent cellular cytotoxicity (ADCC) through CD16, the process of how therapeutic anti-cancer antibodies mediate their activity. The concept of CMV induced adaptive NK cells is new and little is known about these cells in humans. We are optimally positioned to definitively answer the question about whether CMV-induced adaptive NK cells can prime NK cells to treat cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA111412-14
Application #
9672376
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
14
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Cichocki, Frank; Wu, Cheng-Ying; Zhang, Bin et al. (2018) ARID5B regulates metabolic programming in human adaptive NK cells. J Exp Med 215:2379-2395
Grzywacz, Bartosz; Moench, Laura; McKenna Jr, David et al. (2018) Natural Killer Cell Homing and Persistence in the Bone Marrow After Adoptive Immunotherapy Correlates With Better Leukemia Control. J Immunother :
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Williams, Shelly M; Sumstad, Darin; Kadidlo, Diane et al. (2018) Clinical-scale production of cGMP compliant CD3/CD19 cell-depleted NK cells in the evolution of NK cell immunotherapy at a single institution. Transfusion 58:1458-1467
Romee, Rizwan; Cooley, Sarah; Berrien-Elliott, Melissa M et al. (2018) First-in-human phase 1 clinical study of the IL-15 superagonist complex ALT-803 to treat relapse after transplantation. Blood 131:2515-2527

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