The RESPImmun Faculty
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
Project 12: Role of TGF-β ligand signaling in dendritic cells (DC)-dependent immuno-regulation in lung cancer
Co-PI: Anna Birnhuber
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observed in unpublished studies that BMP7 stimulation of human monocyte-derived DCs leads to the up-regulation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
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
- 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.
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
- With Leigh Marsh we will perform murine in vivo validation
experiments and analysis of single cell RNA seq.