Young Investigators

Technical University of Munich
Klinikum rechts der Isar
Klinik und Poliklinik für Innere Medizin III

Ismaninger Str. 22, 81675 München

Phone: +49 89 4140 8066
E-mail: e.orberg[at]tum.de

Title: MyeloBAC: Functional Microbiome Signatures in Response and Resistance to Immunotherapy of Multiple Myeloma

The human intestinal microbiome is a predictor of clinical outcome in stem-cell transplantation (SCT) and response to immunotherapies such as immune-checkpoint blockade. Multiple myeloma (MM) is an incurable plasma cell malignancy in which novel, practice-changing immunotherapies are emerging. Whether microbiome signatures i.e., configurations of microbial communities and their functional output such as microbiota-derived metabolites influence progression or treatment responses in MM remains unclear. The identification of MM-related microbiome signatures may deliver biomarkers to predict and
a template to design future microbiome-based therapies, e.g., dietary interventions or metabolite combination drugs to optimize response rates in MM patients. A better understanding of how the intestinal microbiome is associated with phenotypical and functional changes to anti-tumoral immunity may have a high impact in MM and many other cancers for which we depend on immunotherapy to achieve treatment responses in our patients.

Publications

Chung L, Thiele Orberg E, Geis AL, Chan JL, Fu K, DeStefano Shields CE, Dejea CM, Fathi P, Chen J, Finard BB, Tam AJ, McAllister F, Fan H, Wu X, Ganguly S, Lebid A, Metz P, Van Meerbeke SW, Huso DL, Wick EC, Pardoll DM, Wan F, Wu S, Sears CL, Housseau F.
Bacteroides fragilis Toxin Coordinates a Pro-carcinogenic Inflammatory Cascade via Targeting of Colonic Epithelial Cells.

Cell Host Microbe. 2018Feb 14;23(2):203-214.e5.
Thiele Orberg E, Fan H, Tam AJ, Dejea CM, Destefano Shields CE, Wu S, Chung L, Finard BB, Wu X, Fathi P, Ganguly S, Fu J, Pardoll DM, Sears CL, Housseau F.
The myeloid immune signature of enterotoxigentic Bacteroides fragilis-induced murine colon tumorigenesis.
Mucosal Immunol. 2017 Mar;10(2):421-433.

Centre for Immunoprevention (ZIP)
Division of Animal Physiology and Immunology
Weihenstephaner Berg 3
85354 Freising

Phone: +49 8161 71 3312
carl-philipp.hackstein@tum.de

Title: Development of innate-like and tissue repair-associated features in commensal-reactive T cells

Host-microbiome interactions in the intestine play a crucial role in shaping the development and functional properties of immune cells. Different studies in mice and humans describe the ability of antigens derived from commensal bacteria to induce a broad spectrum of regulatory or effector T cell phenotypes in the intestinal lamina propria differentially impacting inflammation or tissue homeostasis. Adding to this, we recently identified transcriptional signatures and functional properties associated with innate-like T cells in several colonic microbe-reactive T cell populations. These include TCR-independent activation and the expression of tissue repair associated molecules like amphiregulin and vascular endothelial growth factor alpha in response to TCR-stimulation. It is currently unclear, how widespread this innate-like functionality is, what are the underlying mechanisms by which develops, and how it impacts on other immune cells and innate and adaptive immune responses.
To lay the groundwork to fully address these questions, in this project I aim to determine a) the kinetics of the accumulation of commensal-reactive T cells with innate-like and tissue repair-associated properties, b) how the findings apply to commensal-specific T cells with different TCR-specificities and c) if the same transcriptional signatures and functional properties can also be found in human cells.

Technical University of Munich
ZIEL - Institute for Food & Health
Gregor-Mendel-Str. 2
85354 Freising

E-mail: olivia.coleman@tum.de

Title: Functional role of mucus in ATF6-driven microbiota-dependent colorectal cancer

The human body has multiple mechanisms of defense to protect itself from the potentially harmful microorganisms residing in its intestinal lumen. The very first line of defense is the intestinal mucus layer overlying the single layer of enterocytes. Mucus defense mechanisms against bacteria include a physical inner mucus layer barrier, sentinel and intercrypt goblet cell (icGC) responses, and a crypt goblet cell-emptying response. Bergstrom et al. have added a further functional aspect to mucus, demonstrating that proximally derived O-glycosylated mucus encapsulates fecal material and the microbiota to modulate microbiota structure and function. Highly O-glycosylated mucin proteins with their oligosaccharide side chains form a crucial part of microbe-mucus interactions, serving as an interspecies communication facilitators between microbes and the host, and mediators of spatial organization of bacterial communities. Alterations in intestinal mucus have been associated with intestinal diseases, including CRC. In our transgenic mouse model overexpressing activating transcription factor 6 (ATF6) of the endoplasmic reticulum unfolded protein response specifically in intestinal epithelial cells (nATF6^IEC), we observed a spontaneous and microbiota-dependent development of colonic adenomas in homozygous mice. A key characteristic of this CRC mouse model is the aberrant mucus layer seen already at pre-tumor stages. This renders a comprehensive understanding of the complex interplay between ATF6 signaling, the intestinal microbiota and the mucus layer as an essential component towards increasing our mechanistic understanding of disease pathogenesis, and thereby opening new avenues for treatment.