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/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. Theme 3 also aims to understand how the tumor immune microenvironment can dictate the fate (i.e., survival and growth) of cancer cells. An influx of mast cells or dendritic cells in tumors can be either a good or poor prognostic indicator, depending on the type of cancer. Several CCIR members are investigating the influence of the local tumor stroma on mast cell function in terms of promoting or suppressing tumor cell growth and survival. 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 restore or boost anti-tumor immunity in cancer patients.
Some highlights from Fiscal Year 2013 include:
• Immune responses in serial tumor biopsies of patients with metastatic melanoma treated with BRAF-targeted therapy showed that treatment with BRAF inhibition enhances melanoma antigen expression and facilitates T-cell cytotoxicity and a more favorable tumor microenvironment, providing support for potential synergy of BRAF-targeted therapy and immunotherapy (Frederick D, Clin Cancer Res. 2013)
• IL-17F plays a protective role in colon cancer development, possibly via inhibiting tumor angiogenesis (Tong Z, PLoS One 2012)
• Increased levels of proteinase-3 (P3) and NE in myeloid leukemia may favor tolerance because it can lead to cross-presentation of PR1 (a peptide derived from P3 or NE) without activation of the antigen-presenting cell (Alatrash G, J Immunother. 2012)
• The BRAF (V600E) mutation in melanoma cells induces expression of IL-1a and IL-1b, which in turn, upregulates expression of PD-L1, PD-L2 and COX2 in melanoma-associated fibroblasts, endowing them with the ability to suppress anti-tumor CTL activity (Khalili JS, Clin Cancer Res. 2012)
• PR1 cross-presentation on nonhematopoietic tumors such as triple negative breast cancer reveals a novel mechanism linking innate immune cells that are the source of PR1-containing proteases, which are taken up by cancer cells, and anti-tumor adaptive immunity (Mittendorf, Cancer Res. 2012)
• Mesenchymal cells derived from the bone marrow microenvironment enhance engraftment of cord blood-derived stem cells after ex vivo co-culture (de Lima M, N Engl J Med. 2012)
Additional Relevant Publications:
- 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.
- 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.