HIGH MOBILITY GROUP BOX 1 (HMGB1) ENHANCES IMMUNE SUPPRESSION BY REGULATING MYELOID-DERIVED SUPPRESSOR CELL (MDSC) DIFFERENTIATION, FUNCTION, AND SURVIVAL
| dc.contributor.advisor | Ostrand-Rosenberg, Suzanne | |
| dc.contributor.author | Parker, Katherine | |
| dc.contributor.department | Biological Sciences | |
| dc.contributor.program | Biological Sciences | |
| dc.date.accessioned | 2019-10-11T12:34:46Z | |
| dc.date.available | 2019-10-11T12:34:46Z | |
| dc.date.issued | 2015-01-01 | |
| dc.description.abstract | Chronic inflammation is associated with malignant transformation and tumor progression. The immune system also plays a role in tumor progression, with tumor immune escape recognized as a hallmark of cancer. During tumor immune escape, tumor cells produce inflammatory molecules that promote the accumulation and function of myeloid-derived suppressor cells (MDSC). Therefore, inflammation promotes tumor progression through the induction of MDSC, which inhibits the development of anti-tumor immunity. Since the damage associated molecular pattern molecule (DAMP) and alarmin high mobility group box protein 1 (HMGB1) are pro-inflammatory and are binding partners, inducers, and/or chaperones for many of the pro-inflammatory molecules that drive MDSC, we examined HMGB1 as a potential regulator of MDSC. Using murine tumor systems, this dissertations demonstrates that HMGB1 is ubiquitously present in the tumor microenvironment, that HMGB1 can activate MDSC via the NF-?B signal transduction pathway, and that HMGB1 regulates MDSC quantity, quality, and survival. HMGB1 drives MDSC development from bone marrow progenitor cells and promotes MDSC accumulation in the tumor, spleen, and blood of tumor-bearing mice. Additionally, HMGB1 helps MDSC suppress antigen-driven activation of CD4+ and CD8+ T cells, increases MDSC production of the type 2 cytokine IL-10, enhances crosstalk between MDSC and macrophages, and facilitates MDSC'sability to down-regulate expression of the homing receptor L-selectin on naive T cells. It is well appreciated that HMGB1 facilitates tumor cell survival by inducing autophagy. Therefore, we sought to determine if HMGB1 regulates MDSC survival through the induction of autophagy. Inhibition of autophagy or HMGB1 increased the quantity of apoptotic MDSC, demonstrating that autophagy and HMGB1 prolong the survival of tumor-induced MDSC. Circulating tumor-induced MDSC have a default autophagic phenotype, while tumor-infiltrating MDSC are more autophagic. This heightened autophagic state is consistent with the notion that inflammatory conditions within the microenvironment of solid tumors contributes to tumor progression by enhancing immune suppressive MDSC. Taken together, these results demonstrate that the inflammatory molecule HMGB1 contributes to tumor progression by driving the development, function, and viability of MDSC. Therefore, the immunosuppressive activities of HMGB1 must be considered when designing cancer immunotherapies. | |
| dc.genre | dissertations | |
| dc.identifier | doi:10.13016/m2vxer-tbgh | |
| dc.identifier.other | 11362 | |
| dc.identifier.uri | http://hdl.handle.net/11603/15046 | |
| dc.language | en | |
| dc.relation.isAvailableAt | The University of Maryland, Baltimore County (UMBC) | |
| dc.relation.ispartof | UMBC Biological Sciences Department Collection | |
| dc.relation.ispartof | UMBC Theses and Dissertations Collection | |
| dc.relation.ispartof | UMBC Graduate School Collection | |
| dc.relation.ispartof | UMBC Student Collection | |
| dc.rights | This item may be protected under Title 17 of the U.S. Copyright Law. It is made available by UMBC for non-commercial research and education. For permission to publish or reproduce, please see http://aok.lib.umbc.edu/specoll/repro.php or contact Special Collections at speccoll(at)umbc.edu | |
| dc.source | Original File Name: Parker_umbc_0434D_11362.pdf | |
| dc.subject | High Mobility Group Box Protein 1 | |
| dc.subject | Inflammation | |
| dc.subject | Myeloid-derived Suppressor Cells | |
| dc.subject | Tumor immunology | |
| dc.subject | Tumor-induced immune suppression | |
| dc.subject | Tumor microenvironment | |
| dc.title | HIGH MOBILITY GROUP BOX 1 (HMGB1) ENHANCES IMMUNE SUPPRESSION BY REGULATING MYELOID-DERIVED SUPPRESSOR CELL (MDSC) DIFFERENTIATION, FUNCTION, AND SURVIVAL | |
| dc.type | Text | |
| dcterms.accessRights | Distribution Rights granted to UMBC by the author. |