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• Leithner
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• Olschewski A
• Olschewski H
Strobl ⏩
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The RESPImmun Faculty

	Herbert STROBL, MD Role of TGF-β ligand signaling in dendritic cells (DC)-dependent immuno-regulation in lung cancer
Otto Loewi Research Centre, Division of Immunology and Pathophysiology, Medical University of Graz, Heinrichstraße 31a, A-8010 Graz; phone: +43-676-7576195, fax: +43-316-385 79609, ✉ e-mail
websites: [RESPImmun]
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Herbert Strobl is an immunologist and laboratory physician with a major interest in dendritic cell development, myelopoiesis and inflammation. His lab pioneered the generation of Langerhans cells in vitro from human hematopoietic progenitor cells in serum-free culture media. He also described that “left-shifted” band-stage neutrophils can “transdifferentiate&rdquoM into monocyte / macrophages after recruitment to inflammatory lesions. Within RESPImmun he closely collaborates with Grażyna Kwapiszewska, Leigh Marsh (pulmonary inflammation), Horst Olschewski, Gerald Höfler (human patient samples) and Ákos Heinemann (eosinophils and neutrophils in pulmonary inflammation).

Project

Project 12: Role of TGF-β ligand signaling in dendritic cells (DC)-dependent immuno-regulation in lung cancer
Co-PI: Anna Birnhuber

Background

The transforming growth factor beta (TGF-β) family comprises a group of structurally related proteins that include among others TGF-β1/2/3 and several bone morphogenetic proteins (BMPs). The expression of these proteins is tightly regulated during development and tissue homeostasis. Environment-exposed epithelial layers of barrier tissues such as skin and oral mucosa exhibit specific expression pattern of TGF-β1 and BMP7 in the steady-state. We recently showed that BMP7 expression is strongly upregulated within the epidermis in psoriatic lesions. It was recently shown that BMP7 expression by NSCLC cells is negatively correlated with treatment outcome. Two separate signaling cascades involving a limited number of type 1 and type 2 receptors as well as intracellular SMAD proteins are known, i. e. canonical TGF-β versus BMP signaling. We recently observed in unpublished studies that BMP7 stimulation of human monocyte-derived DCs leads to the up-regulation of PDL1 and PDL2. These molecules have previously been implicated in DC-dependent T cell regulation. Moreover, we observed the induction of AXL, a TAM receptor involved in efferocytosis and negative regulation of microbial DC activation. Targeting of the PDL1/PD1 interaction proofed to be an efficient treatment strategy for NSCLC patients.

Hypothesis and objectives

We hypothesize that

enhanced BMP signaling in NSCLC instructs tumor-infiltrating DCs to acquire PDL1, PDL2 and AXL resulting in an augmented immune-regulatory capacity of DCs;
ligands of BMP receptors expressed in the tumor microenvironment instruct cells of the monocyte / DC lineage to acquire a tolerogenic phenotype potentially leading to tumor immune escape;
differential expression of TGF-β ligands and their receptors within the NSCLC tumor microenvironment lead to altered signal strength via the classical TGF-β vs BMP signaling cascades in tumor-infiltrating leukocytes of the monocyte / DC lineage.

Methodology

In years 1 and 2, the PhD student will perform immunohistology stainings of primary human NSLC tumors for BMP7 and other TGF-β ligands, as well as downstream signaling proteins. Singe cell suspensions of tumor tissues versus non-affected lung tissue will be analyzed by FACS for DC associated molecules (PDL1, PDL2, AXL, others). Additionally, available single cell RNA sequ data will be analyzed. In parallel, monocyte-derived DCs and progenitor cell-derived DCs will be stiumulated with TGF-β ligands and the signaling pathways leading to PDL1/2 and AXL induction will be dissected. T cell assays (Treg, Th1/2/17) will be performed and the role of PDL1 / PDL2 and AXL in these assays will be evaluated using inhibitor and/or knock-down strategies. In year 2, tumor infiltrating monocytic cells / DCs and T cells from NSLC patients expressing high and low levels of BMP7 and / or other TGF-β ligands and will be studied phenotypically and functionally. Year 3 – 4: mice lacking specific receptors for TGF-β / BMP family members in CD11c⁺ cells will be analyzed, i. e. lung tumor model, steady-state lung, towards obtaining correlative in vivo data.

Input from collaborations within the RESPImmun programme

Gerald Höfler and Horst Olschewski will provide lung specimen.
With Julia Kargl we will perform phenotypic analyses of tumor associated leukocytes.
With Leigh Marsh we will perform murine in vivo validation experiments and analysis of single cell RNA seq.