Macrophages in human colorectal cancer are pro‐inflammatory and prime T cells towards an anti‐tumour type‐1 inflammatory response

Abstract

High macrophage infiltration into tumours often correlates with poor prognoses; in colorectal, stomach and skin cancers, however, the opposite is observed but the mechanisms behind this phenomenon remain unclear. Here, we sought to understand how tumour-associated macrophages (TAMs) in colorectal cancer execute tumoursuppressive roles. We found that TAMs in a colorectal cancer model were pro-inflammatory and inhibited the proliferation of tumour cells. TAMs also produced chemokines that attract T cells, stimulated proliferation of allogeneic T cells and activated type-1 T cells associated with anti-tumour immune responses. Using colorectal tumour tissues, we verified that TAMs in vivo were indeed pro-inflammatory. Furthermore, the number of tumour-infiltrating T cells correlated with the number of TAMs, suggesting that TAMs could attract T cells; and indeed, type-1 T cells were present in the tumour tissues. Patient clinical data suggested that TAMs exerted tumour-suppressive effects with the help of T cells. Hence, the tumour-suppressive mechanisms of TAMs in colorectal cancer involve the inhibition of tumour cell proliferation alongside the production of pro-inflammatory cytokines, chemokines and promoting type-1 T-cell responses. These new findings would contribute to the development of future cancer immunotherapies based on enhancing the tumour-suppressive properties of TAMs to boost anti-tumour immune responses. To elucidate the roles of TAMs, we first used an in vitro model known as the multi-cellular tumour spheroid (MCTS) model. This model has been proven to exhibit micro-environmental heterogeneity comparable to that of tumours in vivo, in terms of oxygen, nutrient, catabolite and metabolite gradients, resulting in sub-populations of proliferative and necrotic tumour cells typical of non-vascular tumour micro-regions [9,10]. Compared with using animal models, this MCTS model offers the advantages of studying the interactions between tumour cells and TAMs without confounding factors from other cell types, and in a 'human' microenvironment. In this study, we used colorectal cancer as a model to study the mechanisms underlying the tumour-suppressive effects of TAMs. We co-cultured primary human monocytes with human colorectal tumour cells for 8 days as MCTSs, during which time the monocytes would differentiate into TAMs. We performed global gene expression profiling to obtain an overview of the biological functions of TAMs, followed by validation with functional assays. Subsequently, we verified the in vitro findings with tumour tissues from colorectal cancer patients.The TAMs in the colorectal cancer model were pro-inflammatory and inhibited the proliferation of tumour cells. The TAMs also secreted chemokines that attract T cells and expressed surface molecules for antigen presentation and T-cell co-stimulation. In a mixed lymphocyte reaction (MLR) assay, the TAMs stimulated proliferation of allogeneic T cells and activated type-1 T cells, which are associated with anti-tumour immune responses [11]. To co...

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