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Project A3: The role of PDAC-derived extracellular vesicles in tumor immune evasion

Participant:

Prof. Dr. Elke Pogge von Strandmann
Center for Tumor- and Immune Biology (ZTI)
Philipps-Universität Marburg

Project aims:

Natural Killer (NK) cells are involved in cancer immune surveillance and used as effector cells for immunotherapies. Recently, we identified extracellular vesicles such as exosomes as important regulators of NK cell activity. PDAC-released extracellular vesicles (EVs) contribute critically to the formation of the tumor-supporting pre-metastatic liver niche. However, their impact on cytotoxic immune cells (NK cells) and their role in immune escape remains elusive. We hypothesize that PDAC-EVs shape the tumor microenvironment and the immune response to promote tumor progression. The clinical impact of immune-activating EVs expressing BAG6 which engages the Natural Cytotoxicity Receptor NKp30 expressed on NK cells was demonstrated. A clinical trial with NSCLC stage IV patients documented a prolonged progression-free survival upon EV-treatment in a fraction of patients presenting with defective NKp30 expression. This was associated with the rescue of impaired NKp30-dependent NK cell activity and correlated with MHCII and BAG6 expression levels on EVs.

Aim of this project is to unravel the impact of PDAC-EVs on the PDAC-microenvironment and immune evasion with focus on NK cells to develop novel immunotherapeutic approaches. To this end the molecular and functional characterization of EVs derived from wildtype, BAG6-deficient and BAG6 overexpressing pancreatic cell lines (human PANC-1 and mouse Panc02) is planned. A modified cre/lox system will be applied to visualize the uptake of vesicles by target cells in vivo. The phenotype of vesicle-recipient cells will be analyzed by means of mRNAseq and functionally (NK cell subtype, NK cell activity?). We expect differential cellular responses of NK cells upon contact with vesicles from wild-type, BAG6-deficient and proficient cell lines. Moreover, tumor growth, progression and metastasis will be assessed in the transplantation models. Finally, EVs obtained from PDAC patients serum samples will be collected and analyzed regarding amount, composition and NK cell-regulating capacity to correlate this data set with clinical parameters.

The therapeutic potential of immune-stimulatory EVs in combination with an anti-EGFR antibody, which acts via NK cell recruitment will be analyzed using a PDAC mouse model (PKC). It is tempting to speculate that a vesicle-dependent priming of NK cells within the tumor tissue will promote the therapeutic efficacy of the EGFR-blocking antibody in PDAC.

To analyze the impact of EVs tumor immunity we will cooperate with project A1 regarding T cell activity and with project A2 regarding innate immune receptors. We will cooperate with project B1 to study the role of vesicle-associated ADAM8. The project is strongly supported by the Z-project (imaging mouse models, biobank).

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