Understanding the fundamental principles of T-cell programming
T cells play a central role in the control of viral infections and cancer. The spatiotemporal availability of costimulatory molecules contributes to the differential programming of T cells resulting in expansion and differentiation into various subsets. We study how members of the CD28-B7 superfamily and TNFR superfamily (e.g. CD27, OX40 and 4-1BB) cooperate at the molecular level. In addition, we study T-cell fitness properties such as the expansion capacity and cytokine polyfunctionality. Studies include dissection of the molecular programs of T-cell proliferation and differentiation.
Dissection of effector and memory T-cell responses
The capacity of T cells to form effector and memory subsets with different properties is of major interest for its usage in vaccines and immunotherapeutic approaches such as adoptive T-cell therapy. We use various experimental infection models including mouse cytomegalovirus (MCMV), vaccinia virus (VV), lymphocytic choriomeningitis virus (LCMV), Listeria monocytogenes, and we use experimental in vivo tumor models (melanoma, colon cancer, sarcoma, prostate cancer, ovarian cancer and lung cancer) to understand the development and heterogeneity of effector and memory T-cell responses in spatio-temporal settings.
Understanding and improving T-cell based immunotherapy
We aim to understand immunotherapy in a system-wide approach by characterizing in-depth the immune responses to cancer therapy. The analysis encompasses the study of response kinetics in different locations (tumor micro-environment, local and systemic immunity) on both a cellular and molecular level. Studied immunotherapies include (therapeutic) vaccines, immune checkpoint modulators, and chemo-immunotherapy. With respect to the latter, we discovered that cisplatin-based chemotherapy critically depends on the activation of the immune system for sustained tumor protection, and this activation involved the upregulation of costimulatory molecules. Currently, the aim is to decipher how chemotherapeutic agents interact in the programming of T cells. Another research line aims to improve adoptive T-cell therapy (ACT) by integrating the costimulation expertise with metabolic programming to improve the fitness of T cells.
All three themes cover the spectrum from molecular and gene editing technology in vitro/ex vivo to in vivo experimental models for human disease and the use of human samples. For the in-depth characterization of the immune response on a molecular and cellular level we use high-dimensional single cell profiling technologies including CyTOF mass cytometry (CyTOF) and (single-cell) RNA sequencing. To allow exploration of the biological markers and parameters that relate to immunotherapy, we generate novel computational analysis tools to understand the cellular immune response and associated clinical response (Beyrend et al., J Vis Exp. 2019; Beyrend et al., Comput Struct Biotechnol J. 2018). In addition, we use gain-of-function and loss-of-function tools such as transgenic and knockout mice, CRISPR-Cas gene editing, immunomodulating antibodies, and MHC multimer technology.