Innate immune cells such as macrophages and neutrophils can promote or hinder tumor growth, but it is not known how these opposing activities are regulated in the tumor microenvironment. The major goal of this grant is to elucidate the mechanisms by which innate cells are activated to destroy tumor cells. To study how tumors may activate innate immunity, we have produced matched sets of tumor cell lines that are rejected by the immune system (termed regressors) or grow progressively (termed progressors) when transplanted into syngeneic, na?ve, wild-type mice. We have performed comparative studies to identify key immune system components that are enriched in tumors that undergo rejection compared to tumors that grow progressively. Using flow cytometry, immunohistochemistry, and microarray analysis, we have identified activated macrophages, neutrophils, nitric oxide, and the cytokine IL-17D as participants in tumor rejection.
Our specific aims seek to understand the mechanism by which these cells and molecules interact to effect tumor rejection. The principle hypothesis states that IL-17D produced in the tumor microenvironment recruits neutrophils and activates macrophages to eliminate tumor cells via nitric oxide production.
Specific aim 1 will study the role of IL-17D in shaping innate and adaptive anti-tumor responses. We will modulate IL-17D levels in tumor cells and observe the effect on tumor growth and immune cell infiltration.
Specific aim 2 will explore how macrophages can promote tumor rejection by measuring macrophage tumoricidal activity in vitro and in vivo. We will compare macrophages isolated from regressor versus progressor tumors.
Specific aim 3 will examine neutrophil effector pathways that are elicited by regressor tumors. These studies will enhance the efficacy of cytokine-based anti-tumor immunotherapeutic approaches while providing inroads into how innate immune cells can eliminate developing tumors.
This research addresses how the innate immune system attacks tumor cells. We are testing the idea that certain cytokines produced by the tumor cell itself can lead to activation of innate immune cells. Our studies will provide a method to enhance cancer treatment by harnessing the power of the immune system.
|Doedens, Andrew L; Rubinstein, Mark P; Gross, Emilie T et al. (2016) Molecular Programming of Tumor-Infiltrating CD8+ T Cells and IL15 Resistance. Cancer Immunol Res 4:799-811|
|Saddawi-Konefka, Robert; Seelige, Ruth; Gross, Emilie T E et al. (2016) Nrf2 Induces IL-17D to Mediate Tumor and Virus Surveillance. Cell Rep 16:2348-58|
|Seelige, Ruth; Washington Jr, Allen; Bui, Jack D (2016) The ancient cytokine IL-17D is regulated by Nrf2 and mediates tumor and virus surveillance. Cytokine 91:10-12|
|Banno, Asoka; Garcia, Daniel A; van Baarsel, Eric D et al. (2016) Downregulation of 26S proteasome catalytic activity promotes epithelial-mesenchymal transition. Oncotarget 7:21527-41|
|Boland, Brigid S; Widjaja, Christella E; Banno, Asoka et al. (2015) Immunodeficiency and autoimmune enterocolopathy linked to NFAT5 haploinsufficiency. J Immunol 194:2551-60|
|O'Sullivan, Timothy; Saddawi-Konefka, Robert; Gross, Emilie et al. (2014) Interleukin-17D mediates tumor rejection through recruitment of natural killer cells. Cell Rep 7:989-98|
|Shin, June Ho; Zhang, Luhua; Murillo-Sauca, Oihana et al. (2013) Modulation of natural killer cell antitumor activity by the aryl hydrocarbon receptor. Proc Natl Acad Sci U S A 110:12391-6|
|Peinado, Carlos; Kang, Xi; Hardamon, Chanae et al. (2013) The nuclear factor-ÎºB pathway down-regulates expression of the NKG2D ligand H60a in vitro: implications for use of nuclear factor-ÎºB inhibitors in cancer therapy. Immunology 139:265-74|
|O'Sullivan, Timothy; Saddawi-Konefka, Robert; Vermi, William et al. (2012) Cancer immunoediting by the innate immune system in the absence of adaptive immunity. J Exp Med 209:1869-82|