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Identifying Strategies to Manipulate the Immune System to Increase the Control of Tumors and Metastases

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New cues in anti-cancer immunity

European scientists investigated how our immune system responds to cancer formation. Their observations opened up new avenues for designing immunotherapeutic approaches.

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Normally, our immune system recognises and eliminates foreign pathogens through T cell activation via dendritic cells. This, however, is not always the case during cancer, suggesting that the tumour microenvironment somehow inhibits proper T cell activation. To overcome such poor immunogenicity, therapeutic strategies have been developed using dendritic cells loaded ex vivo with tumour-associated antigens. Yet, this approach has limited clinical efficacy indicating that a better understanding of dendritic cell biology and function is urgently required. In this context, the EU-funded (ISMISICOTAM) project set out to provide fundamental insight and improve the outcome of dendritic cell vaccination. Their long term objective was to find ways to restrict the growth of tumours and metastases using the immune system. Researchers wished to investigate whether tumour location influences its immunogenicity. For this purpose, they generated novel cancer models where tumours where implanted either in the dermis, containing multiple dendritic cell subsets, or in the subcutaneous tissue, mainly composed of fat. Experiments revealed that intradermal but not subcutaneous tumours are rapidly rejected. Insight into the mechanism indicated that this rejection was mediated by dendritic cells that infiltrate the tumour site and activate T cells. However, in subcutaneous tumours, dendritic cells recruitment is delayed and thus tumours overgrow the immune response. Analysis of the architecture of established subcutaneous tumours using fluorescent microscopy revealed that dendritic cells reside largely in the tumour periphery within a dense and linear collagen network. Only a few cells moved inside the tumour bed along collagen extensions, suggesting that extracellular matrix organisation plays a key role in dendritic cell mobilisation within tumours. This suggests that modulation of the collagen network could affect tumour immunogenicity. Collectively, the results of the ISMISICOTAM project bring us a step closer to understanding tumour immunology. The generated knowledge could be exploited in clinical immunology to design new strategies for improving cancer patient treatments.

Keywords

Immune system, immunotherapy, cancer, dendritic cells, T cells

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