Tumors invoke immunosuppression in the host by inducing an altered profile of cytokine expression. The crucial regulatory cytokine IL-12 operates as a bridge between innate and adaptive immunities. It is produced by macrophages and dendritic cells, and acts upon NK and T cells to induce their production of IFN-gamma, driving T cells to develop Th1 responses. IL-12 has also been recognized to exhibit strong anti-tumor properties. Therefore, by blocking IL-12 expression, the tumor might guarantee its own survival. The possibility of a tumor-induced downregulation of IL-12 gene expression as a tumor survival strategy has been scarcely explored. The long-term goal of my research is to clarify the role of macrophages in mammary tumor development. We have shown that the mouse mammary tumor D1-DMBA-3 directly produces factors, and induces B cells and macrophages from the host to produce factors that inhibit the production of IL-12 by peritoneal elicited macrophages from tumor-bearing animals. I hypothesize that these tumor-associated factors, in particular the tumor-produced phospholipids phosphatidylserine (PS) and the tumor-induced pro-inflammatory cytokine IL-6, exert their immunosuppressive effects at least in part by downregulating IL-12 gene expression at the transcriptional level in macrophages, resulting in evasion of the host's immune defenses and enhanced tumor growth. The objective of the present application is to reveal the molecular mechanisms of the D1-DMBA-3 tumor-mediated inhibition of IL-12 gene expression in macrophages from tumor-bearing animals. I plan to test my hypothesis by pursuing the following specific aims: 1) To elucidate the mechanisms by which the presence of the D1-DMBA-3 tumor, and specifically the tumor-derived factor phosphatidylserine (PS) and the tumor-induced cytokine IL-6, downregulate the production of IL-12 in macrophages from tumor-bearing animals as well as in macrophages from normal mice pretreated with these tumor-associated factors, respectively; 2) To investigate the consequences of manipulating the expression of the critical IL-12-inducing transcription factors NFkB and C/EBP on IL-12 expression in macrophages from normal and tumor-bearing animals, as well as in macrophages from normal mice pretreated with PS and IL-6; 3) To determine the effects of modulating PS and IL-6 in vivo on IL-12 production and mammary tumor progression. These studies constitute a first step towards the goal of manipulating the levels of IL-12 in tumor hosts, leading to appropriate immune activation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01CA101926-03
Application #
7455298
Study Section
Special Emphasis Panel (ZCA1-RTRB-A (M2))
Program Officer
Ojeifo, John O
Project Start
2006-07-01
Project End
2011-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
3
Fiscal Year
2008
Total Cost
$153,873
Indirect Cost
Name
University of Miami School of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Torroella-Kouri, Marta; Rodríguez, Dayron; Caso, Raul (2013) Alterations in macrophages and monocytes from tumor-bearing mice: evidence of local and systemic immune impairment. Immunol Res 57:86-98
Rodríguez, Dayron; Silvera, Risset; Carrio, Roberto et al. (2013) Tumor microenvironment profoundly modifies functional status of macrophages: peritoneal and tumor-associated macrophages are two very different subpopulations. Cell Immunol 283:51-60
Perry, Giselle; Iragavarapu-Charyulu, Viyaya; Harhaj, Edward W et al. (2010) Role of the proteasome in the downregulation of transcription factors NFkappaB and C/EBP in macrophages from tumor hosts. Oncol Rep 23:875-81
Caso, Raul; Silvera, Risset; Carrio, Roberto et al. (2010) Blood monocytes from mammary tumor-bearing mice: early targets of tumor-induced immune suppression? Int J Oncol 37:891-900
Torroella-Kouri, Marta; Silvera, Risset; Rodriguez, Dayron et al. (2009) Identification of a subpopulation of macrophages in mammary tumor-bearing mice that are neither M1 nor M2 and are less differentiated. Cancer Res 69:4800-9