ISMISICOTAM

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

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 Obiettivo del progetto (Objective)

'The number of cancer patients is increasing and effective treatments are still limited. The identification of tumor associated antigens (TAA) has allowed for the stimulation of the immune system to recognize and destroy solid tumors. The most common strategy is to increase tumor specific cytotoxic CD8 T cell responses by vaccination of the patient with dendritic cells (DCs) pulsed with TAA peptides. Despite a great deal of efforts, these therapies have not proven efficient at complete rejection of tumors and metastases. While CD8 T cells have been at the center stage of anti-tumor immunotherapies, the role of CD4 T cells in tumor immunity has remained largely underappreciated, although some reports have shown that CD4 T cells alone are able to protect against transplanted tumors in mice. Given the multiplicity of CD4 T cell functions, finding ways to enhance productive anti-tumor CD4 T cell response is of tremendous therapeutic interest. This proposal aims at identifying strategies to manipulate the immune system for increasing the control of tumors and metastases. Emphasis will be put on the interactions between CD4 T cells, DCs, and Natural Killer (NK) cells. The project will address the following questions: (1) Are solid tumors overall poorly immunogenic for CD4 T cells? (2) What cells are relevant at the tumor and draining lymph node sites for the TAA uptake and presentation? (3) Can one enhance anti-tumor CD4 T cell responses by manipulating NK cell functions? If so, is the increase of CD4 T cell responses beneficial for the control of both the tumors and metastasis? To answer these questions, I will use molecular biology, cellular immunology and in situ imaging of the anti-tumor response by microscopy. Overall, I expect the results to lead to major advancements within the field of tumor immunology, and to possible translation to clinic.'

Introduzione (Teaser)

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

Descrizione progetto (Article)

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.