Author ORCID Identifier
https://orcid.org/0000-0002-7568-8167
Date of Graduation
12-2020
Document Type
Dissertation (PhD)
Program Affiliation
Immunology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Shao-Cong Sun, Ph.D.
Committee Member
Kimberly S. Schluns, Ph.D.
Committee Member
Gregory Lizee, Ph.D.
Committee Member
Florencia McAllister, M.D.
Committee Member
Jagannadha Sastry, Ph.D.
Committee Member
Joya Chandra, Ph.D.
Abstract
ELUCIDATING THE ROLES OF IL-15 IN THE TUMOR MICROENVIRONMENT
Rosa M. Santana Carrero, B.S.
Advisory Professors: Shao-Cong Sun, Ph.D. & Kimberly S. Schluns, Ph.D.
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) 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.
Keywords
Interleukin 15, STING, Immunology, Melanoma, Colon Cancer, Intratumoral Agents, Immune Checkpoints