The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access)
Author ORCID Identifier
Date of Graduation
Doctor of Philosophy (PhD)
Shao-Cong Sun, Ph.D.
Kimberly S. Schluns, Ph.D.
Gregory Lizee, Ph.D.
Florencia McAllister, M.D.
Jagannadha Sastry, Ph.D.
Joya Chandra, Ph.D.
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.
Interleukin 15, STING, Immunology, Melanoma, Colon Cancer, Intratumoral Agents, Immune Checkpoints