Immunosuppressive networks in the tumour environment and their therapeutic relevance

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Abstract
The pathological interactions between cancer cells and host immune cells in the tumour microenvironment create an immunosuppressive network that promotes tumour growth, protects the tumour from immune attack and attenuates immunotherapeutic efficacy. Poor tumour-associated antigen (TAA)-specific immunity is not simply due to a passive process whereby adaptive immunity is shielded from detecting TAAs. There is an active process of 'tolerization' taking place in the tumour microenvironment. Tumour tolerization is the result of imbalances in the tumour microenvironment, including alterations in antigen-presenting-cell subsets, co-stimulatory and co-inhibitory molecule alterations and altered ratios of effector T cells and regulatory T cells. Human tumorigenesis is a slow process that can occur over several years and in this respect is similar to chronic infection. The lack of an acute phase in the course of tumorigenesis might profoundly shape T-cell immune responses, including the quality of antigen release, T-cell priming and activation. Current immunotherapies often target patients with advanced-stage tumours, which have high levels of inflammatory molecules, cytokines, chemokines, tumour-infiltrating T cells, dendritic cells and macrophages. It is arguable whether we need to incorporate more of these components into tumour treatments. Immune tolerization is predominant in the immune system in patients with advanced-stage tumours. It is time to consider combinatorial tumour therapies, including those that subvert the immune-tolerizing conditions within the tumour.