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The tumor microenvironment in pancreatic ductal adenocarcinoma: current perspectives and future directions

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies and is characterized by a unique tumor microenvironment (TME) consisting of an abundant stromal component. Many features contained with the PDAC stroma contribute to resistance to cytotoxic and immunotherapeutic regimens, as well as the propensity for this tumor to metastasize. At the cellular level, PDAC cells crosstalk with a complex mixture of non-neoplastic cell types including fibroblasts, endothelial cells, and immune cells. These intricate interactions fuel the progression and therapeutic resistance of this aggressive cancer. Moreover, data suggest the polarization of these cell types, in particular immune and fibroblast populations, dictate how PDAC tumors grow, metastasize, and respond to therapy. As a result, current research is focused on how to best target these populations to render tumors responsive to treatment. Herein, we summarize the cell populations implicated in providing a supporting role for the development and progression of PDAC. We focus on stromal fibroblasts and immune subsets that have been widely researched. We discuss factors which govern the phenotype of these populations and provide insight on how they have been targeted therapeutically. This review provides an overview of the tumor microenvironment and postulates that cellular and soluble factors within the microenvironment can be specifically targeted to improve patient outcomes.

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Acknowledgements

The authors would like to thank all of the patients and families who continue to participate in and support clinical research. Further, the authors recognize all members of the Lesinski lab as important contributors to this manuscript through fruitful discussions regarding the intricacies of the PDAC TME. BioRender was used to generate all figures present in this work.

Funding

This work was supported by NIH grants R01CA208253, R01CA228406, and P30CA138292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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  1. Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, 1365 Clifton Road NE, Atlanta, 30322, GA, USA

    Cameron J. Herting, Isaac Karpovsky & Gregory B. Lesinski

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  1. Cameron J. Herting
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  2. Isaac Karpovsky
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Correspondence to Gregory B. Lesinski.

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Dr. Lesinski has consulted for ProDa Biotech, LLC, and received compensation. Dr. Lesinski has received research funding through a sponsored research agreement between Emory University and Merck and Co., Bristol-Myers Squibb, Boerhinger-Ingelheim, and Vaccinex. Dr. Herting and Mr. Karpovsky have no conflicts to disclose.

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Herting, C.J., Karpovsky, I. & Lesinski, G.B. The tumor microenvironment in pancreatic ductal adenocarcinoma: current perspectives and future directions. Cancer Metastasis Rev 40, 675–689 (2021). https://doi.org/10.1007/s10555-021-09988-w

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