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: