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.
","abstract_html":"<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>","abstract_has_math":false,"creators":["Santana Carrero, Rosa Maria","https://orcid.org/0000-0002-7568-8167
"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation (PhD)","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Shao-Cong Sun, Ph.D.","Kimberly S. Schluns, Ph.D.","Gregory Lizee, Ph.D."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2020,"date_issued":"2020-12-01T08:00:00Z","date_published":"2020-12-01T08:00:00Z","updated_at":"2026-07-24T05:50:38Z","subjects":["Interleukin 15","STING","Immunology","Melanoma","Colon Cancer","Intratumoral Agents","Immune Checkpoints","Immunity","Immunology and Infectious Disease","Immunotherapy","Medicine and Health Sciences"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1057","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Shao-Cong Sun, Ph.D.","Kimberly S. Schluns, Ph.D.","Gregory Lizee, Ph.D."]},{"key":"dc:creator","label":"Author","values":["Santana Carrero, Rosa Maria","https://orcid.org/0000-0002-7568-8167
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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.
"]},{"key":"dc:title","label":"Title","values":["Elucidating The Roles of Il-15 In The Tumor Microenvironment"]}]}],"canonical_facts":{"dc:contributor":["Shao-Cong Sun, Ph.D.","Kimberly S. Schluns, Ph.D.","Gregory Lizee, Ph.D."],"dc:creator":["Santana Carrero, Rosa Maria","https://orcid.org/0000-0002-7568-8167
"],"dc:date.available":["2020-12-17T08:00:00Z"],"dc:description.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.
"],"dc:identifier":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1057"],"dc:subject":["Interleukin 15","STING","Immunology","Melanoma","Colon Cancer","Intratumoral Agents","Immune Checkpoints","Immunity","Immunology and Infectious Disease","Immunotherapy","Medicine and Health Sciences"],"dc:title":["Elucidating The Roles of Il-15 In The Tumor Microenvironment"],"thesis:degree_level":["Dissertation (PhD)"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T05:50:38Z"}