Epithelial cell-controlled Treg in tissue/immune crosstalk and intestinal tumor growth

• Applicant: Ana Izcue, Ph.D.
• Subject Area: Immunology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 449790317

The immune system can eliminate cancer. Tumors can alter their environment to promote their own survival, for example by misusing the body’s anti-inflammatory mechanisms. CD4+ Foxp3+ regulatory T cells (Treg) are one of these mechanisms. They accumulate in tumors and are instrumental to prevent tumor rejection.Despite a large number of studies on the interplay between Tregs and tumors, the pathways controlling Treg accumulation and survival in tumor tissues, as well as the specific characteristics of tumor Tregs are still poorly understood and plagued by inconsistencies. This is partly due to the complex processes that take place during cancer, which result in heterogeneous tumor models where it is difficult to distinguish primary tumor-induced from secondary immune changes.We have recently identified a model of tamoxifen-induced epithelial activation of the canonical Wnt signalling pathway that allows to address the effects of tumor-related changes on immune regulation while avoiding many of the pitfalls of other models. In this model, tamoxifen-induced CreERT-mediated recombination in gut epithelial cells generates a stabilized form of beta-catenin that mimics canonical Wnt signals, a hallmark of early carcinogenic events in intestinal tumors. This model offers various advantages over currently used models to study Treg manipulation by the tumor environment:- It reproducibly induces a robust and rapid Treg accumulation- It is induced by changes in epithelial cells that are independent of previous immune reactions- It mimics early events in cancer progression and therefore represent primary effects- It specifically triggers the accumulation of an distinct effector Treg subsetWe will combine this model with other systems, including a mouse model of spontaneous intestinal tumors and samples from colon cancer patients. Our preliminary results suggest that the model of activated epithelial cells is representative of tumor/immune interactions, because the same specific Treg subset can also be detected in other tumor models, although in lower absolute numbers. The changes we induce in our animal model are similar to changes that occur in human patients, at the early stages of most colorectal tumors. Moreover, our own preliminary data suggest that a similar specific Treg subpopulation also accumulates in human tumors and therefore that our models reflect the situation in patients.We want to use this model to determine the pathways mediating epithelial control of the immune system in precancerous settings. We will also assess the consequences of Treg accumulation on the growth of secondary tumors, and perform a detailed side by side comparison of mouse and human Treg and cytotoxic cells in tumors.Taken together, this project will shed light on the interplay between tumoral transformation and immune regulation.

• DFG Programme: Research Grants