Osteoclast Activated Super-Charged NK Cells Preferentially And Rapidly Expand CD8+ T Cells From Cancer Patients And BLT Humanized Mice
SUMMARY
UCLA researchers in the School of Dentistry have developed a novel strategy to expand highly functional natural killer cells and to expand large number of CD8+ T cells using super-charged natural killer cells.
BACKGROUND
Natural killer (NK) cells are known to target cancer stem cells and undifferentiated tumors. Medium and high cytotoxic activity of peripheral-blood lymphocytes are associated with reduced cancer risk, and high NK cell infiltration of the tumor is associated with better prognosis, whereas low activity is associated with increased cancer risk. Function of NK cells tend to be significantly suppressed in tumor patients due to downregulation of NK receptors in the tumor microenvironment.
Several in vitro NK expansion techniques, and various methods to obtainex vivo-expanded, activated and CD3+ T cell-depleted NK cells have been developed to establish the safety and efficacy of adoptive cellular transfer of human leukocyte antigen (HLA)-haploidentical NK cells in patients with advanced cancer. However, immunotherapy with NK cells is limited due to inability to obtain sufficient number of highly functional NK cells for therapeutic dose. In addition, current approaches based on expansion of patient NK cells and those from tumor-bearing humanized mice, is significantly limited due to the expansion of a small fraction of contaminating T cells which crowd out NK cells by their faster proliferating capability.
INNOVATION
Researchers at UCLA have developed a novel method for expanding large numbers of super-charged NK cells with significant potential to lyse and differentiate cancer stem cells. These researchers found that decline in cytotoxicity and lower interferon γ (IFN-γ) secretion by NK cells from cancer patients and tumor-bearing BLT humanized mice correlates with faster expansion of CD8+ T cells from residual contaminating T cells within purified NK cells during culture with osteoclasts, whereas healthy donors’ osteoclasts continue expanding super-charged NK cells while limiting CD8+ T cell expansion. In contrast, dendritic cells are found to promote faster expansion of CD4+ T cells by the NK cells, resulting in the decline in NK cells numbers from healthy individuals. Addition of anti-CD3 monoclonal antibody inhibits T cell proliferation while enhancing NK cell expansion with lower cytotoxicity but higher secretion of IFN-γ. Most importantly, osteoclast expanded super-charged NK cells preferentially expanded CD8+ T cells in both healthy and cancer patients. These findings set the foundation that will give rise to sub-population of NK, CD8+ T cells or CD4+ T cells depending on the type of expansion for infusion in cancer patients. This method may also be used for expansion of antigen-specific T cells.
APPLICATIONS
- Expand natural killer cells for cancer immunotherapy
- Preferentially increase the numbers and function of CD8+ T cells
- Enhance the levels of antigen-specific CD8+ T cells
- Generate memory CD8+ T cells
ADVANTAGES
This method specifically expand CD8+ T cells or CD4+ T cells depending on the type of expansion.
STATE OF DEVELOPMENT
This method has been tested in vitro.
RELATED MATERIALS
Kaur, K., Cook, J., Park, S.H., Topchyan, P., Kozlowska, A., Ohanian, N., Fang, C., Nishimura, I. and Jewett, A., Novel Strategy to Expand Super-Charged NK Cells with Significant Potential to Lyse and Differentiate Cancer Stem Cells: Differences in NK Expansion and Function between Healthy and Cancer Patients, Frontiers in Immunology, 2017.