Inhibitory receptor repertoire of anti-tumoral NK cells in mouse MHC-I-deficient cancers
Immunology
Final Report Abstract
NK cells are promising targets for cancer immunotherapeutic approaches, since they posses the capacity to rapidly recognize and eliminate malignant cells without prior sensitization. The activation of NK cells is dependent on an array of inhibitory and activating surface receptors. One way of NK cell activation is the recognition of “missing self” with the help of MHC-I specific inhibitory receptors of the Ly49 family. The present study focused on the examination of Ly49 receptor patterns on intra-tumoral NK cells. Dr. Wiedemann found, that intra-tumoral NK cells expressing several inhibitory Ly49 receptors had a more activated phenotype as compared to NK cells expressing no inhibitory Ly49 receptors. However, NK cells expressing inhibitory receptors were reduced over time within the tumor. This reduction was accompanied by a decreased abundance of nuclear pSTAT5. STAT5 is a transcription factor, which is crucial for NK cell survival, proliferation and cytotoxicity. Dr. Wiedemann thus focused on defining the role of STAT5 signaling in these intra-tumoral NK cells. She found that NK cells with reduced levels of STAT5 display reduced levels of surface Ly49 receptors. Stimulation with IL-2 and IL-15 two major cytokines upstream STAT5 in NK cells, lead to STAT5 binding to a high number of genomic putative enhancer regions, followed by dynamic changes of the epigenetic and transcriptional landscape. STAT5 target genes included not only Ly49 genes, but also genes encoding survival and cytotoxic functions. In order to therapeutically use these findings for ex vivo stimulation of NK cells prior to adoptive transfer, murine and human NK cells were stimulated with different cytokine combinations and examined for transcriptional and epigenetic changes. Dr. Wiedemann found, that STAT5 shared a great number of genomic regions bound by STAT1 or STAT4 and that STAT5-mediated signaling enhanced the transcriptional response to STAT1 and STAT4 signaling. Final computational analyses of these data sets are still ongoing, but the results of the applicant’s studies will provide further insight into how NK can be more efficiently used in tumor therapy. To conclude, Dr. Wiedemann found that STAT5 not only plays a role in NK cell survival, but also promotes phenotypic changes and supports transcriptional and epigenetic modifications, which, in combination with other cytokines like IL-12, can increase NK cell activation and functionality.
Publications
- Memory responses of innate lymphocytes and parallels with T cells. Review. Seminars in Immunopathology, 2018
Rapp M, Wiedemann GM, Sun JC
(See online at https://doi.org/10.1007/s00281-018-0686-9)
