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Evoking anti-tumor immunity in pancreatic cancer

Ziel

Immunotherapies have transformed outcomes across a range of cancers, but not pancreatic ductal adenocarcinoma (PDAC). Recent evidence suggests that PDAC tumors form distinct, context-dependent immunosuppressive niches, but the signals and drivers that control them are still largely enigmatic.

We created unique resources and tools to investigate and target the distinct principles by which PDAC subtypes evade immune destruction, and propose to use them in 3 complementary approaches:

First, we will utilize novel in vivo models reflecting the distinct PDAC immunophenotypes we identified and combine them with novel spatial single-cell barcoding, tracing and perturbation strategies we developed (SpaceMap). This allows us to monitor immunosuppression and -activation dynamics and myeloid (neutrophil and macrophage) mediated cancer cell killing (PhagoQuant) in vivo under basal and therapeutic conditions. These results will lead to the first spatially and temporally resolved atlas of PDAC-immune niche interaction dynamics and function.

Second, we will functionalize the key executors of immunosuppression, neutrophils and macrophages, and perturb their recruitment, retention and polarization into highly immunosuppressive states. These functional studies will uncover the signals that orchestrate distinct myeloid-driven modes of immunosuppression and uncover new ways to reprogram them toward immune activation and cancer cell killing.

Third, we will develop strategies to increase T cell recruitment, persistence and (re)activation, and combine them with myeloid reprogramming and cancer cell targeted therapies, to develop rationale multimodal combinations that evoke durable anti-tumor immunity.

This work will provide fundamental insights into the regulatory principles and dynamic circuits that control the distinct modes of immunosuppression PDAC subtypes utilize to evade immune destruction and will open fundamental new therapeutic horizons for immune-assisted PDAC eradication.

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Finanzierungsplan

HORIZON-ERC - HORIZON ERC Grants

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Aufforderung zur Vorschlagseinreichung

(öffnet in neuem Fenster) ERC-2025-ADG

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Gastgebende Einrichtung

DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG
Netto-EU-Beitrag
€ 2 497 125,00
Adresse
IM NEUENHEIMER FELD 280
69120 Heidelberg
Deutschland
Region
Baden-Württemberg Karlsruhe Heidelberg, Stadtkreis
Aktivitätstyp
Research Organisations
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Keine Daten

Begünstigte (1)