6A, white arrows). The percentage of T cells that were IFN-γ+ in each patient sample varied from 33 to 90% (Fig. 6B and Table 1). selleck chemicals llc Taken together, the presence of pro-inflammatory

TAMs and type-1 T cells, and the correlation of numbers of TAMs and T cells in the primary tissue sections support our in vitro findings (Figs. 3 and 4). We aimed to elucidate the mechanisms underlying the tumour-suppressive effects of TAMs in colorectal cancer, an important but under-studied property of TAMs. We found that TAMs in the colorectal cancer model were pro-inflammatory (Fig. 3B). Pro-inflammatory TAMs have been associated with anti-tumour properties, such as production of cytotoxic products such as reactive oxygen intermediates, serine proteases and lytic factors, and enhanced the ability to process and present tumour antigens to T cells 2, 6, 16. Notably, IFN-γ was amongst the pro-inflammatory cytokines secreted by the colorectal TAMs, in the co-cultures as well as in vivo (Fig. 5A). This is an important observation as the production of IFN-γ has been mainly associated with type-1 T cells or NK cells 17. www.selleckchem.com/products/bay-57-1293.html Activated macrophages can secrete IFN-γ, but at lower levels 18. IFN-γ is a potent anti-tumour cytokine; its production has been highly correlated with tumour

regression in immunotherapy 17. Recently, IFN-γ has been shown to switch tumour-promoting, anti-inflammatory (M2-like) TAMs to the tumour-suppressive, pro-inflammatory (M1-like) phenotype 19, 20, supporting the hypothesis that T-cell responses orchestrate TAM polarisation early on during cancer development 8. Here, our data suggest an alternative: TAMs can produce IFN-γ and other pro-inflammatory cytokines to create a pro-inflammatory microenvironment which activates type-1 T cells, which in turn produce more IFN-γ (Figs. 4–6). IFN-γ can elicit other Fenbendazole downstream anti-tumour immune responses, such as sensitising tumour

cells to apoptosis 17, potentiating monocyte cytotoxicity against tumour cells 21 and anti-angiogenic activities in vivo 22. Notably, the production of the tumour-promoting angiogenic factor, VEGF, by the tumour cells was suppressed by the colorectal TAMs in co-cultures (Fig. 3B). Besides promoting angiogenesis, VEGF has been associated with increased risk of relapse in colorectal cancer patients 23. VEGF also exerts other undesirable tumour-promoting effects, such as decreasing production of cytotoxic mediators like granzyme B and perforin by T cells, and decreasing TNF-α and IFN-γ secretion by NK cells 24. Additionally, VEGF promotes the infiltration of immune-suppressive cells such as myeloid-derived suppressor cells and regulatory T cells into tumours 25, which facilitate tumour growth. In fact, clinical studies have shown VEGF to be a valid therapeutic target for colorectal cancer 12.