The role of the biophysical properties of the tumor stroma in T-cell infiltration and anti-tumoral responses

• Applicant: Professorin Susana Minguet, Ph.D.
• Subject Area: Hematology, Oncology ; Immunology
• Term: from 2015 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 276845045

T cell-based immunotherapy of cancer is one of the latest scientific breakthroughs. Indeed, T cells can recognize antigens expressed by tumor cells, consequently being activated and killing the tumor cells. However, to date the success of T cell-based cancer immunotherapy is mainly limited to hematopoietic tumors. In contrast, in solid tumors the malignant cells are surrounded by an extracellular matrix (ECM) that prevents T cells from accessing the tumor cells. The requirements and properties of the ECM for efficient T-cell infiltration are poorly investigated. We have recently reported that expression of Caveolin-1 (Cav1) by tumor-associated fibroblasts increases their contractility remodeling the ECM architecture and producing organized and stiff matrices that facilitate tumor cell migration, invasion and metastasis. How this Cav1-mediated remodeling influences anti-tumoral T-cell responses has not been investigated. Thus, the microenvironments generated in the presence or absence of Cav1 provide a powerful and unique tool to investigate how the biophysical properties of the ECM influence T-cell infiltration in solid tumors and thus, tumor rejection. In this proposal, we present an ambitious and interdisciplinary research project using in vitro, ex vivo and in vivo approaches to understand the interaction interplay between the biophysical properties of the tumor-associated ECM and T-cell migration of specific T cell subsets (including primary human alpha beta and gamma delta T cells). In addition, we aim to target T cells by a gene therapy-based approach to increase their migration potential and thus, to render the architecture of the tumor microenvironment more permissive to T-cell infiltration. Moreover, we will use human tissue microarrays of primary tumors and healthy tissues to correlate the rate of T-cell infiltration to the expression of Cav1 in the fibroblastic stroma. Thus, we aim to explore if stromal Cav1 expression could also be a potential indicator of the suitability of anti-cancer immunotherapy using T lymphocytes. All together, we aim to contribute to a better understanding of the complex interplay between the biophysical properties of the ECM and T-cell infiltration, and thus aid to the improvement of the existing or development of novel therapeutics against solid tumors.

• DFG Programme: Research Grants