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

Final Report Summary - ISMISICOTAM (Identifying Strategies to Manipulate the Immune System to Increase the Control of Tumors and Metastases)

Context of the study
Our study aims at identifying strategies to manipulate the immune system for increasing the control of developing tumors and metastases.
Tumor immunogenicity is defined as the ability of a tumor to induce a protective immune response. Typically, naive T cells circulate from the blood to the secondary lymphoid organs where their interaction with dendritic cells (DC) presenting antigens (Ag) captured from the periphery dictates the induction of an immune response, or tolerance. In the context of a growing tumor, the tumor environment may inhibit proper activation of T cells by affecting DC function or alternatively by limiting leukocytes access to the tumor environment through densification of the extra-cellular matrix surrounding the tumor bed.
To circumvent some of these problems, an immunotherapeutic strategy is to vaccinate the patient with DC generated ex vivo and loaded with tumor Ag to activate tumor-specific T cells. However, these tests only induce good clinical responses for a minority of patients. This limited success may be explained by the choice of DC preparation and route of administration. One alternative strategy is to improve the natural presentation of tumor Ag by the patient’s DC in vivo. Hence, a better knowledge of DC biology in the context of developing tumors is crucial for designing more comprehensive DC-based vaccination.

Summary description of the project objectives
The vast majority of studies focusing on anti-tumor immune responses in mouse models are performed with tumors transplanted subcutaneously. However, DC have only been described in the dermis and nothing is known regarding their frequencies in the sub-cutaneous tissue, mainly composed of fat. Our first objective was to determine whether the anatomical site where a tumor develops could influence its immunogenicity.
Numerous studies have revealed the heterogeneity of the DC network in lymphoid and non-lymphoid tissues, both at phenotypic and functional levels. Our second objective was to characterize the DC subsets that are relevant at the tumor and draining lymph nodes (dLN) sites for the tumor Ag uptake and presentation to T cells.
The longer term objective of this project is to find ways to increase the control of tumors and metastases by T cells. Exciting results obtained in Objectives 1 and 2 have led us to focus on the pathways of DC recruitment to tumors and the molecular mechanisms guiding these cells in the tumor environment.


Summary description of the results obtained
In order to better understand the cues favoring DC recruitment to tumors and efficient Ag presentation in draining lymph nodes (dLN), we first analyzed the impact of the anatomical site of tumor development on tumor immunogenicity. We implanted tumor cells either in the dermis (epithelial environment) or in the subcutaneous tissue (interstitial environment) of immunocompetent mice. We showed that intradermal (i.d.) but not subcutaneous (s.c.) tumors, are rapidly rejected in a T cell-dependent manner and induce protective effector and memory T cells.
We then characterized the DC subsets that are relevant in the tumor dLN for tumor Ag presentation to T cells. Of note, we showed that the rejection of i.d. tumors correlates with rapid recruitment of dermal DC presenting the tumor Ag to both CD4 and CD8 T cells in the dLN. The same DC subsets were mobilized upon s.c. tumor transplantation but with delayed kinetics. Moreover, we showed a delayed and poor infiltration by DC in s.c. tumors as compared with i.d. tumors. Hence, the different kinetics of DC recruitment to the dLN may reflect an upstream differential DC recruitment to the tumor bed.
To study the endogenous DC dynamic behavior within the tumor architecture, we set up a model of live tumor explants analysis by 2-P fluorescent microscopy. We showed that endogenous DC are preferentially intertwined with a dense and linear collagen network in the tumor periphery and some DC localize and move along collagen extensions within the tumor bed.

Conclusions and socio-economic impact
Altogether our results suggest that in the skin, dermal DC are recruited from the adjacent tissue to the tumor bed with displacement ruled by the extracellular matrix organization. Modulation of the collagen network could affect, either positively or negatively, the DC infiltration within tumors. The final results could have a major impact in clinical immunology as they could lead to new strategies for improving cancer patients treatments (i.e. strategies to improve tumor infiltration by DC for optimizing tumor Ag presentation to T cells), thus reducing the costs of actual long-term therapies.