Tumor microenvironment and immunotherapy
T cell-based immunotherapy of cancer is one of the latest scientific breakthroughs. T cells can recognize antigens expressed by tumor cells, consequently being activated and killing the tumor cells. The investigation of the molecular mechanisms to activate T cells making them more efficient killers is one of the hallmarks of the field. Most of these efforts are focused on ab T cells, however, our investigations have focused in another type of T cells, namely gd T cells. These cells are significantly less abundant in peripheral blood, their expansion ex vivo is more challenging and our knowledge of their functioning is much more reduced. However, these cells are HLA-independent, cytotoxic, and they are activated by stress-induced self-antigens, lipids, or pyrophosphates overproduced by tumor cells. Together with the group of Prof. Schamel, we reported the molecular composition of the human gd TCR back in 2005. We have recently discovered that in strong contrast to the ab TCR, the gd TCR does not undergo the CD3 conformational change upon natural ligand binding. However, the gd TCR has the intrinsic capacity to perform this structural change as we demonstrated by identifying a specific antibody, which induced this change when bound to the TCR. Most importantly, this synthetic induction of the conformational change results in a significant increase in the cytotoxicity against tumor cells of clonally expanded human gd T cells. Now, we focus in developing synthetic approaches to induce this conformational change “on command” in collaboration with the group of Prof. Weber (Prof. for Synthetic Biology, BIOSS, Freiburg).
Importantly, gd T cells are also highly interesting for anti-cancer immunotherapies because they have afferent responses (they do not need to get previously activated in the lymph node) and normally migrate in microenvironments enriched in extracellular matrix (ECM) components. This last aspect is of vital importance in the treatment of solid tumors, in which the malignant cells are surrounded by a highly organized ECM preventing T cells from accessing the tumor cells. We have recently reported that expression of Cav1 by tumor-associated fibroblasts increases their contractility, thereby 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 provides 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.
This project is awarded with a DFG individual grant (2016-2018).
- Dopfer EP, Oberg HH, Siegers GM, Fiala GJ, Garcillán B, Regueiro JR, Kabelitz D, Adams EJ, Minguet S, Wesch D, Fisch and Schamel WWA. “The CD3 conformational change is not required for gd T cell receptor activation, but enhances tumor killing”. Cell Rep. 2014 (5):1704.
- Goetz JG*, Minguet S*, Navarro I, Samaniego R, Tello M, Calvo E, Lazcano JJ, Osteso T, Pellinen T, Echarri A, Cerezo A, Garcia R, Keely PJ, Sánchez-Mateos P, Cukierman E, Del Pozo MA. Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastais. Cell. 2011 (146):148-63. *Shared first authorship.
- Siegers, GM, Swamy M, Fernández-Malavé E, Minguet S, Rathmann S, Guardo AC, Pérez-Flores V, Regueiro JR, Alarcón B, Fisch P, Schamel WW. Different composition of the human and the mouse gd T cell receptor CD3 explains different phenotypes of CD3g- and CD3d-immunodeficiencies. Journal of Experimental Medicine 2007 (11):2537-44.