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.

NF-κB and Pancreatic Cancer; Chapter and Verse

“…Therefore, the micro-environment is potentially a source of targetable NF-κB vulnerabilities, and an immunotherapeutic “Achilles heel” [ 219 , 228 ]. Treatment targets based on modulation of the PDAC microenvironment are now being assessed in combination with standard chemotherapies [ 50 , 77 , 229 ].…”

Adaptations and Advancement of Biologic Immunotherapy in the Management of Immunologically Cold Solid Malignancies

“…Extensive modern trials encompassing GVAX (pro-GM-CSF) for pancreatic and prostate cancer 56,57 demonstrate a significant increase in host recruitment and tumour infiltration of CD8+ T-lymphocytes, with correspondingly significant increases in patient survival and disease state (p<0.02) alongside PD-1 inhibition. 58,59 Whereas large-scale follow-up remains vital to elucidate applicability of cancer vaccines as a means of augmenting low levels of foundation immune response to cold tumours, ongoing studies strongly suggest such vaccinations may cotransform nonresponsive cold cancer populations towards TIL-inflammation through direct effect while also expanding checkpoint inhibitor functionality through multiplication of relevant special-effector T-lymphocytes. 60 However, difficulties to practising fully-personalised cancer vaccination alongside immunotherapy endure, which outside of practical implications in resource or time investment is further constrained by advanced disease realities such as patients' deficient T-cell function and incomplete response to initial vaccination.…”

CXCL10/CXCR3 signaling contributes to an inflammatory microenvironment and its blockade enhances progression of murine pancreatic precancerous lesions

“…Pancreatic cancer is difficult to target because its fibrotic microenvironment not only acts as a barrier for delivery of tumor cell targeting drugs, but it also generates an anti-inflammatory environment and prevents immunotherapy ( Balachandran et al, 2019 ). One of the current paradigms for treatment of PDA focuses on combining chemotherapy with immune modulators that reprogram tumor-promoting macrophages toward a pro-inflammatory phenotype ( Bastea et al, 2019 ; Mitchem et al, 2013 ; Pandey and Storz, 2019 ). A deeper understanding of the mechanisms that play a role in macrophage polarization can provide insights to develop such new interventions.…”