Abstract SY32-04: Defects in T cell migration within tumors: a role for extracellular matrix architecture

Abstract

Abstract T cell-based immunotherapies have given promising results in patients with metastatic melanoma. However, a significant proportion of cancer patients did not respond to these therapeutic interventions for reasons that are not understood. To attack a tumor, T cells need to be correctly primed in the tumor-draining lymph nodes, enter into the tumor, navigate within the tumor environment and then mediate their effector functions to cause destruction of cancer cells. All of these criteria that rely on proper migration of T cells must be met for a treatment to be effective. By using fluorescence imaging techniques, we have made significant progress in the understanding of how T cells are blocked in their migratory activities and have identified several obstacles. The first occurs in tumor-draining lymph nodes as our data reveal the existence of marked cellular and structural changes that limit T cells from migrating and performing their surveillance activity. Another alteration concerns the poor ability of T cells to contact malignant cells within tumors. Indeed, in several human carcinomas, T cells are far from malignant cells but enriched in the stroma composed of non-tumors cells along with the extracellular matrix. We have identified the matrix structure as an important stromal component in controlling the ability of T cell to migrate and mount antitumor immune response. Whereas reticular fiber networks favor T cell navigation, dense and aligned matrix fibers act as unfavorable migration zones for T cells. Such fibrotic structures, which are frequently observed around tumor islets, contribute to the poor capacity of T cells to contact and kill tumor cells. Thus, abnormal extracellular matrix, as observed in solid tumors, can be considered another important player of the tumor stroma involved in blocking T cells in their antitumor activities. A new challenge in cancer therapy will be to develop approaches aimed at altering the architecture of the tumor stroma rendering it more permissive to antitumor T cells. Citation Format: Emmanuel Donnadieu. Defects in T cell migration within tumors: a role for extracellular matrix architecture. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY32-04. doi:10.1158/1538-7445.AM2014-SY32-04