Targeting the tumor microenvironment in pancreatic ductal adenocarcinoma

ABSTRACT

Introduction: The dismally slow improvement in patient survival over the years for pancreatic cancer patients is mainly due to two factors: the late diagnosis, at which point the disease is spread to distant organs; and the fact that tumor cells are surrounded by a dense, highly immunosuppressive microenvironment. The tumor microenvironment not only shields pancreatic cancer cells from chemotherapy but also leaves it unsusceptible to various immunotherapeutic strategies that have been proven successful in other types of cancer.

Areas covered: This review highlights the main components of the pancreatic tumor microenvironment, how they cross-talk with each other to generate stroma and promote tumor growth. Additionally, we discuss the most promising treatment targets in the microenvironment whose modulation can be robustly tested in combination with standard of care chemotherapy. Currently, active clinical trials for pancreatic cancer involving components of the microenvironment are also listed.

Expert opinion: Although immunotherapeutic approaches involving checkpoint inhibition are being pursued enthusiastically, there is still more work to be done with several other emerging immune targets that could provide therapeutic benefit.

KEYWORDS:

• Pancreatic cancer
• tumor microenvironment
• stellate cells
• fibroblasts
• tumor-associated macrophages
• myeloid derived suppressor cells

Article highlights

• Desmoplasia in the stromal microenvironment makes up to ~80% of total tumor mass in PDAC, creating a physical barrier and conferring chemoresistance

• Pancreatic TME is largely non-immunogenic and tumor-promoting in nature

• PSCs, CAFs, MDSCs, and TAMs are major cellular components of the TME, that cross-talk amongst each other and with tumor cells to activate signaling pathways beneficial to tumor growth and metastasis

• Remodeling of the stroma to enhance anti-tumor immunity requires simultaneous targeting of TME and tumor cells

• Majority of ongoing clinical trials for PDAC are utilizing small molecule inhibitors and monoclonal antibodies targeting TME along with frontline chemotherapy

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by a grant from the National Institutes of Health (CA200572) to P Storz.