About the program

The Sibilia Lab at the Center for Cancer Research is using genetically engineered mouse models (GEMMs), patient material, primary cells and organoids to dissect the molecular mechanisms underlying the immune system’s ability to combat cancer. Our goal is to characterize how oncogenic mutations and epigenetic modifications modulate the tumor microenvironment (TME) to identify novel points of intervention in the TME to reactivate the immune response against tumors. The TME is comprised of various stromal and innate and adaptive immune cells that infiltrate tumors and manipulate immune responses and we have a particular interest in innate cells like dendritic cells (DCs) and various subtypes of myeloid cells (macrophages).

A mechanistic understanding of how to modulate these cells to enhance anti-tumor immunity is of fundamental importance to improve immune-based anti-cancer treatment in patients. Our lab employs state-of-the-art technologies and multi-omics approaches: e.g. scRNA-Seq, CHIP/ATAC-Seq, multi-colour flow cytometry, cell sorting, genome engineering (Lentiviral, CRISPR/Cas9), multiplex immunofluorescence.

We have 2 PhD positions addressing the following questions:

1. How can we modulate innate immunity to convert cold (immunosuppressive) tumors into hot (immunogenic) tumors?
2. How are Ras mutations in tumors conferring therapy resistance via the TME?

The lung microenvironment is composed by structural and immune cells, which together shape the activity and plasticity of tissue resident macrophages. The Sylvia Knapp group and others discovered that rare innate immune cell populations, like ILC2s, eosinophils, basophils or mast cells, regulate the homeostatic phenotype of alveolar macrophages, the functionality of which is essential in the response to respiratory infections. Any alteration in this response can result in impaired defense and/or exaggerated inflammation upon viral infection. The Sylvia Knapp group will follow the hypothesis that rare innate immune cells contribute to the responsiveness of lung macrophages to viral infections. Understanding the intricate interplay of regulatory immune cells and their impact on macrophage functionalities upon viral lung infections will enable to fine tune immune responses and prevent severe disease manifestations as currently seen in some COVID-19 patients.

Candida albicans is among the most prevalent opportunistic human fungal pathogens and is an important cause of mortality also because of increased drug resistance. It leads to diseases such as disseminated and chronic cutaneous candidiasis, particularly in immunocompromised patients. Lots in known on Candida immunity for systemic and mucosal surface infections, while knowledge about the skin immune defence is limited. The BS group has shown that the absence of the cytokine signal transducing kinase TYK2 improves topical clearance of C. albicans and suppresses dissemination to distal organs. Aim of this project is to address how TYK2 signalling in specific cell types, such as skin-resident T cells, orchestrates the immune defence against cutaneous C. albicans infection. This study will not only contribute to the mechanistic understanding of signalling networks controlling C. albicans skin infections and invasive disease, but may unravel novel and urgently needed immune modulatory treatment options.

The mechanisms underlying metastasis formation by some but not other tumors are poorly understood but are likely due to heterogeneity between individual tumor cells and their complex interaction with the tumor microenvironment and subsequent remodeling of metastatic niches. Besides their immune-suppressive phenotypes, myeloid cells seem particularly important in establishing pre- and metastatic niches, thereby enabling successful colonization and outgrowth of metastasis. Less studied, however, is the role of myeloid cells in establishing anti-metastatic niches that may prevent metastasis.

In the Winkler Lab, the successful Ph.D. candidate will dissect tumor-immune cell interaction networks to identify mechanisms of anti-metastatic niche remodeling using spatial omics applications. A better understanding of these protective cell interactions is crucial for developing novel therapies that may prevent metastasis in high-risk patients or directly help patients with metastatic disease.

Some CD4⁺ T-cell subsets display cytotoxic activity (CD4 CTLs), thus breaking the functional dichotomy of CD4⁺ helper and CD8⁺ cytotoxic T-cells. CD4 CTLs are generated during viral infections and anti-tumour immunity in humans and mice. Moreover, CD4 CTLs might also cause immunopathology in autoimmune diseases. However, the molecular mechanism regulating their differentiation is poorly understood. Naïve CD4⁺ T-cells transferred into RAG2-KO mice differentiate into CD4⁺CD8αα⁺ CTLs in the small intestine, thus providing an ideal experimental system to study CD4 CTL differentiation. In this PhD project, we will investigate novel mechanisms regulating CD4 CTL differentiation, focusing on epigenetic and transcriptional regulation. Understanding these mechanisms will reveal novel approaches for therapeutic induction of CD4 CTLs.

Transcription of inflammatory response genes is strictly signal-dependent and must be tightly controlled to prevent spurious immune activation and auto-immunity. How this control is achieved given the inherent leakiness and noisiness of transcription is currently poorly understood. We hypothesize that one or more molecular mechanisms exist that limit transcriptional noise at the level of single genes with key functions in controlling and eliciting innate immune responses. Since the mechanisms limiting transcriptional heterogeneity in innate immune cells are currently poorly characterized, the results of this project might have profound implications for both our fundamental knowledge as well as how these might represent risk-factors to auto-immune diseases.

During chronic infection and tumorigenesis CD8⁺ T cells display progressive loss of effector function, widely known as T cell exhaustion. As a member of the SHIELD doctoral program, my group will elucidate the molecular mechanisms underlying T cell exhaustion, particularly focusing on the role of transcriptional and epigenetic regulators.

We will utilize various immunological methods, cutting edge approaches in molecular biology and mouse genetic tools. Our study might thereby provide insight into novel therapeutic approaches against chronic infection and tumor, given that the epigenetic inflexibility of exhausted T cells is a major barrier for effective immunotherapy. Being embedded in the multidisciplinary educational program in immunology, the successful candidate will gain a deep understanding of T cell-mediated immune responses during the PhD study.

Gut microbiota modulate the immune system and affect human health, ranging from the response to cancer therapies as well as the onset of autoimmune diseases. Antibody responses against (gut) microbiota have been shown to play a key role in mediating this microbiota-immune axis, with cross-reactive antibodies/molecular mimicry between microbial and human proteins being involved in autoimmune disease. However, the actual antigens recognized by antibodies are vastly unknown. By using a newly developed technology, TV will unravel the functional capacity of this enormous immune repertoire targeting microbiota and investigate their role in modulating cancer immunotherapy response as well as immune mediated diseases (IMDs).

In cutaneous lupus erythematosus (CLE) autoreactive T cells play a major role in tissue inflammation and organ damage. Georg Stary has shown that tissue-resident T cells can survive in the tissue independently of the circulation for more than a decade, contribute to inflammation while being therapeutically hard to reach and exit the skin to participate in inflammation in distant organs. The distribution between circulating and tissue-resident T cells in CLE and their specificity remain elusive. Georg Stary will follow the hypothesis that TCR clones of pathogenic T cells recognizing auto-antigens are found within the tissue-resident T cell pool in CLE patients and contribute to systemic disease. Identification of pathogenic tissue-resident T cells, their T cell antigens and specific immunodominant epitopes is crucial for understanding disease pathophysiology and can help designing targeted therapies.

Rheumatoid arthritis (RA) is a chronic inflammatory disease leading to irreversible joint destruction involving various cell types. Although T cell targeted therapies have been shown to be effective, the exact role of CD4+ T cells to inflammation and tissue destruction remains unclear.

The laboratory of Michael Bonelli has successfully established a T cell dependent arthritis model. Histological analysis reveal synovial tissue inflammation and joint destruction similarly to RA patients. The research team will therefore investigate if and to which extent CD4+ T cells drive the development of inflammatory joint diseases. Using next generation sequencing technologies from human and mouse samples in combination with functional assays will allow to identify the factors that drive pathogenicity of T cells. Understanding the mechanisms that drive the development of pathogenic T cells and their role in inflammatory arthritis will be crucial to identify new treatment targets and develop T cell targeted therapies.

The hair follicle (HF) is an important mammalian structure and its stem cells are protected by an “immune privilege” mechanism maintained by the absence/low expression of MHC-I and secretion of anti-inflammatory factors. Thomas Bauer showed that EGFR secures HF integrity during hair eruption protecting the HF from microbial invasion, its destruction and skin inflammation, all manifestations also seen in cancer patients receiving EGFR-inhibitors and patients with EGFR mutations. Preliminary data from TB identified that MHC-I is upregulated on EGFR deficient HF stem cells prior to their destruction. He will investigate if and by which molecular mechanism the HF immune privilege is protected by using GEMMs lacking EGFR in different HF cells. This will uncover networks and interactions at the basis of immune evasion that might be exploited also by cancer cells and possibly identify targets preventing anti-cancer therapy side effects and hair loss.