Reprogramming of immune cells in the tumor microenvironment

• Applicant: Professor Dr. Joachim L. Schultze, since 10/2017
• Subject Area: Hematology, Oncology
• Term: from 2015 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 269749094

Tumorigenesis is a complex process influencing cells in close vicinity but also acting systemically. Studies in humans and autochthonous murine tumor models have clearly revealed that the tumor microenvironment plays an important role during tumorigenesis. Most tumors are characterized by an immunosuppressive tumor microenvironment (TME) which is often associated with an accumulation of tumor-infiltrating macrophages and an expansion of regulatory T cells (Treg cells) resulting in global immunosuppression. Simultaneously, anti-tumor immunity is further impaired by the induction of tolerance in effector T cells. To shift the balance towards effective anti-tumor immunity, two principles have been applied: on the one hand, the adaptive transfer of tumor-specific effector cells or the induction of such cells by tumor vaccination, on the other hand the deletion of the existing immune response in the TME. Based on our own observations and findings we suggest a third way by reprogramming the existing immune response in the TME to induce efficient antitumor immunity.In our previous work, we could show that the expression of SATB1 in Treg cells needs to be suppressed for these cells to exert inhibitory function. In contrast, SATB1 must be induced for T cells to gain effector properties. The global chromatin organizer SATB1 seems to be central for T cells to decide between effector and suppressive functions. In fact, overexpression of SATB1 in Treg cells leads to a loss of suppression while at the same time these cells gain effector function. We now want to exploit the role of SATB1 as a central switch of T-cell differentiation therapeutically by reprogramming T cells via Satb1 in the tumor microenvironment of the murine Eµ-TCL1 model. Using genetic models, we will first assess this by overexpressing Satb1 in all CD4+ T cells and subsequently specifically in Treg cells and monitor tumor growth, immune cell function, and anti-tumor immunity. At the same time, we want to understand the influence of reprogramming based on SATB1 in other immune cells. We will test this first in macrophages since these are one of the major cell types in the TME. If reprogramming of immune cells leads to reduced tumor incidence or reduced tumor progression, we will also assess potential systemic effects of this approach. Taken together, we want to introduce a novel and alternative immunotherapeutic strategy by reverting immunosuppression in the tumor microenvironment by reprogramming CD4+ T cells to induce an anti-tumor immune response through targeting Satb1 expression.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Privatdozent Dr. Marc Beyer, until 10/2017