Elucidating The Roles of Il-15 In The Tumor Microenvironment

<p>ELUCIDATING THE ROLES OF IL-15 IN THE TUMOR MICROENVIRONMENT</p> <p>Rosa M. Santana Carrero, B.S.</p> <p>Advisory Professors: Shao-Cong Sun, Ph.D. & Kimberly S. Schluns, Ph.D.</p> <p>Interleukin-15 (IL-15) is a factor that promotes activation, proliferation, cytotoxicity, and survival of CD8 T cells and NK cells, and has been shown to have anti-tumor effects. Moreover, loss of IL-15 expression in human colorectal tumors correlates with increased risk of relapse, diminished survival, decreased density and proliferation of T cells. All together these findings suggest that IL-15 expressed locally in the tumor microenvironment (TME)<strong><em> </em></strong>is an important mediator of anti-tumor responses by tumor infiltrating lymphocytes (TILs) representing a potentially powerful immunotherapeutic target. Unfortunately, the regulation and roles of IL-15 within the TME is unclear. I hypothesized that IL-15 produced in the TME is an important factor promoting anti-tumor responses by cytotoxic lymphocytes stimulating their optimal numbers, enhancing their effector functions and metabolic fitness. In this dissertation I investigated the cellular sources and regulation of IL-15 in the TME and its roles in enhancing anti-tumor immunity. I showed, using several murine tumor models, that soluble IL-15/IL-15Ra complexes (sIL-15 complexes) are present at high levels in the interstitial fluid of early tumors and decrease with tumor growth. Depletion of local IL-15 in tumors led to decreased numbers of TILs without directly affecting tumor growth, likely by promoting their infiltration into tumors. I also found that levels of sIL-15 complexes could be upregulated in advanced tumors by local activation of the Stimulator of Interferon Genes (STING) pathway. While treatment of tumors with STING agonists induces tumor regression, optimal STING-mediated systemic anti-tumor immunity required IL-15 expression. In addition, I examined the direct effect of IL-15 agonists in poorly T-cell infiltrated tumors and found that recombinant sIL-15/IL-15Ra-Fc complexes (rsIL-15c) and a polymer-conjugated IL-15R agonist significantly slowed tumor growth and increased the total numbers of TILs. Moreover, intratumoral IL-15 agonists in combination with anti-CTLA-4 immune checkpoint blockade synergistically induced better tumor growth control and enhanced mouse survival in a poorly infiltrated melanoma tumor model. These findings reveal the ability of IL-15 expressed within the TME to regulate TIL numbers and upon upregulation by inflammatory signals, contribute to enhanced anti-tumor responses.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2020

Authors dc:creator

• Santana Carrero, Rosa Maria
• <p>https://orcid.org/0000-0002-7568-8167</p>

Contributors dc:contributor

• Shao-Cong Sun, Ph.D.
• Kimberly S. Schluns, Ph.D.
• Gregory Lizee, Ph.D.

• Interleukin 15
• STING
• Immunology
• Melanoma
• Colon Cancer
• Intratumoral Agents
• Immune Checkpoints
• Immunity
• Immunology and Infectious Disease
• Immunotherapy
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1057

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2113