Context-Specific Determinants of the Immunosuppressive Tumor Microenvironment in Pancreatic Cancer

Author:

Falcomatà Chiara123ORCID,Bärthel Stefanie123ORCID,Schneider Günter1234ORCID,Rad Roland356ORCID,Schmidt-Supprian Marc367ORCID,Saur Dieter123ORCID

Affiliation:

1. 1Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.

2. 2Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany.

3. 3Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.

4. 4University Medical Center Göttingen, Department of General, Visceral and Pediatric Surgery, Göttingen, Germany.

5. 5Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technische Universität München, Munich, Germany.

6. 6German Cancer Consortium (DKTK), Heidelberg, Germany.

7. 7Institute of Experimental Hematology, School of Medicine, Technical University of Munich, Munich, Germany.

Abstract

AbstractImmunotherapies have shown benefits across a range of human cancers, but not pancreatic ductal adenocarcinoma (PDAC). Recent evidence suggests that the immunosuppressive tumor microenvironment (TME) constitutes an important roadblock to their efficacy. The landscape of the TME differs substantially across PDAC subtypes, indicating context-specific principles of immunosuppression. In this review, we discuss how PDAC cells, the local TME, and systemic host and environmental factors drive immunosuppression in context. We argue that unraveling the mechanistic drivers of the context-specific modes of immunosuppression will open new possibilities to target PDAC more efficiently by using multimodal (immuno)therapeutic interventions.Significance:Immunosuppression is an almost universal hallmark of pancreatic cancer, although this tumor entity is highly heterogeneous across its different subtypes and phenotypes. Here, we provide evidence that the diverse TME of pancreatic cancer is a central executor of various different context-dependent modes of immunosuppression, and discuss key challenges and novel opportunities to uncover, functionalize, and target the central drivers and functional nodes of immunosuppression for therapeutic exploitation.

Funder

Deutsche Forschungsgemeinschaft

Wilhelm Sander-Stiftung

HORIZON EUROPE European Research Council

Publisher

American Association for Cancer Research (AACR)

Subject

Oncology

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