Theme 3: Inflammation and the tumor immune microenvironment
Overview: Since chronic inflammation is associated with the formation of several types of cancer, several CCIR members study the physiological versus pathological roles of NF-kB signaling pathways, Th17 cells and the IL-17 family of pro-inflammatory cytokines (IL-17A – IL-17F) in preventing/forming cancer and autoimmune disease. Several CCIR members are investigating how the local tumor stroma influences mast cell function in terms of promoting or suppressing tumor cell growth and survival based on previous observations that an influx of mast cells in tumors can be either a good or poor prognostic indicator, depending on the type of cancer. And finally, CCIR members are investigating mechanisms by which tumor cells induce T cell tolerance or responses. Results of these studies will be translated to find ways enabling immunotherapy to induce, restore or boost anti-tumor immunity in cancer patients.
Relevant Publications (recent - 2008):Khalili JS, Liu S, Rodriguez-Cruz TG, Whittington M, Wardell S, Liu C, Zhang M, Cooper ZA, Frederick DT, Li Y, Zhang M, Joseph RW, Bernatchez C, Ekmekcioglu S, Grimm E, Radvanyi LG, Davis RE, Davies MA, Wargo JA, Hwu P, Lizee G. Oncogenic BRAF(V600E) Promotes Stromal Cell-Mediated Immunosuppression Via Induction of Interleukin-1 in Melanoma. Clin Cancer Res. 2012,18(19):5329-40.
Tong Z, Yang XO, Yan H, Liu W, Niu X, Shi Y, Fang W, Xiong B, Wan Y, Dong C. A protective role by interleukin-17F in colon tumorigenesis. PLoS One. 2012, 7(4):e34959.
Wu RC, Liu S, Chacon JA, Wu S, Li Y, Sukhumalchandra P, Murray JL, Molldrem JJ, Hwu P, Pircher H, Lizee G, Radvanyi LG. Detection and characterization of a novel subset of CD8+CD57+ T cells in metastatic melanoma with an incompletely differentiated phenotype. Clin Cancer Res. 2012,18(9):2465-77.
Chang SH, Reynolds JM, Pappu BP, Chen G, Martinez GJ, Dong C. Interleukin-17C promotes Th17 cell responses and autoimmune disease via interleukin-17 receptor E. Immunity. 2011, 35(4):611-21. PubMed PMID: 21982598.
Chang DZ, Ma Y, Ji B, Wang H, Deng D, Liu Y, Abbruzzese JL, Liu YJ, Logsdon CD, Hwu P. Mast cells in tumor microenvironment promotes the in vivo growth of pancreatic ductal adenocarcinoma. Clin Cancer Res. 2011,17(22):7015-23. PubMed PMID: 21976550.
Xu T, Wang X, Zhong B, Nurieva RI, Ding S, Dong C. Ursolic acid suppresses interleukin-17 (IL-17) production by selectively antagonizing the function of RORgamma t protein. J Biol Chem. 2011, 286(26):22707-10. PubMed PMID: 21566134; PubMed Central PMCID: PMC3123037.
Martin-Orozco N, Li Y, Wang Y, Liu S, Hwu P, Liu YJ, Dong C, Radvanyi L. Melanoma cells express ICOS ligand to promote the activation and expansion of T-regulatory cells. Cancer Res. 2010, 70(23):9581-90.
Chacon-Salinas R, Limon-Flores AY, Chavez-Blanco AD, Gonzalez-Estrada A, Ullrich SE. Mast cell-derived IL-10 suppresses germinal center formation by affecting T follicular helper cell function. J Immunol. 2011, 186(1):25-31. .
Chang SH, Chung Y, Dong C. Vitamin D suppresses Th17 cytokine production by inducing C/EBP homologous protein (CHOP) expression. J Biol Chem. 2010, 285(50):38751-5.
Fukunaga A, Khaskhely NM, Ma Y, Sreevidya CS, Taguchi K, Nishigori C, Ullrich SE. Langerhans cells serve as immunoregulatory cells by activating NKT cells. J Immunol. 2010, 185(8):4633-40. .
Reynolds JM, Pappu BP, Peng J, Martinez GJ, Zhang Y, Chung Y, Ma L, Yang XO, Nurieva RI, Tian Q, Dong C. Toll-like receptor 2 signaling in CD4(+) T lymphocytes promotes T helper 17 responses and regulates the pathogenesis of autoimmune disease. Immunity. 2010, 32(5):692-702.
Peng J, Yang XO, Chang SH, Yang J, Dong C. IL-23 signaling enhances Th2 polarization and regulates allergic airway inflammation. Cell Res. 2010, 20(1):62-71.
Martin-Orozco N, Muranski P, Chung Y, Yang XO, Yamazaki T, Lu S, Hwu P, Restifo NP, Overwijk WW, Dong C. T helper 17 cells promote cytotoxic T cell activation in tumor immunity. Immunity. 2009, 31(5):787-98.
Nurieva R, Yang XO, Chung Y, Dong C. Cutting edge: in vitro generated Th17 cells maintain their cytokine expression program in normal but not lymphopenic hosts. J Immunol. 2009, 182(5):2565-8.
Martin-Orozco N, Chung Y, Chang SH, Wang YH, Dong C. Th17 cells promote pancreatic inflammation but only induce diabetes efficiently in lymphopenic hosts after conversion into Th1 cells. Eur J Immunol. 2009, 39(1):216-24.
Yamazaki T, Yang XO, Chung Y, Fukunaga A, Nurieva R, Pappu B, Martin-Orozco N, Kang HS, Ma L, Panopoulos AD, Craig S, Watowich SS, Jetten AM, Tian Q, Dong C. CCR6 regulates the migration of inflammatory and regulatory T cells. J Immunol. 2008, 181(12):8391-401. .
Byrne SN, Limon-Flores AY, Ullrich SE. Mast cell migration from the skin to the draining lymph nodes upon ultraviolet irradiation represents a key step in the induction of immune suppression. J Immunol. 2008, 180(7):4648-55. .
Fukunaga A, Khaskhely NM, Sreevidya CS, Byrne SN, Ullrich SE. Dermal dendritic cells, and not Langerhans cells, play an essential role in inducing an immune response. J Immunol. 2008, 180(5):3057-64.