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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Transplantation, Tolerance, and Tumor Immunology (TTT)
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Howcroft, Thomas K
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University of California San Diego
Schools of Medicine
La Jolla
United States
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Meier, Angela; Gross, Emilie T E; Schilling, Jan M et al. (2018) Isoflurane Impacts Murine Melanoma Growth in a Sex-Specific, Immune-Dependent Manner: A Brief Report. Anesth Analg 126:1910-1913
Searles, Stephen C; Santosa, Endi K; Bui, Jack D (2018) Cell-cell fusion as a mechanism of DNA exchange in cancer. Oncotarget 9:6156-6173
Seelige, Ruth; Saddawi-Konefka, Robert; Adams, Nicholas M et al. (2018) Interleukin-17D and Nrf2 mediate initial innate immune cell recruitment and restrict MCMV infection. Sci Rep 8:13670
Seelige, Ruth; Searles, Stephen; Bui, Jack D (2018) Innate sensing of cancer's non-immunologic hallmarks. Curr Opin Immunol 50:1-8
Fong, Jerry J; Tsai, Chih-Ming; Saha, Sudeshna et al. (2018) Siglec-7 engagement by GBS ?-protein suppresses pyroptotic cell death of natural killer cells. Proc Natl Acad Sci U S A 115:10410-10415
Strnadel, Jan; Choi, Sunkyu; Fujimura, Ken et al. (2017) eIF5A-PEAK1 Signaling Regulates YAP1/TAZ Protein Expression and Pancreatic Cancer Cell Growth. Cancer Res 77:1997-2007
Seelige, Ruth; Washington Jr, Allen; Bui, Jack D (2017) The ancient cytokine IL-17D is regulated by Nrf2 and mediates tumor and virus surveillance. Cytokine 91:10-12
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
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
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

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