The tumor microenvironment of pancreatic adenocarcinoma and immune checkpoint inhibitor resistance: a perplex relationship

Abstract

Pancreatic cancer is one of the most aggressive cancers with a high mortality rate even among patients with early-stage disease. Although recent studies with novel therapeutic approaches have led to modest improvement in survival outcomes, limited progress is achieved for the use of immunotherapeutics in this challenging cancer. Immune checkpoint inhibitors, thus far, single-agent or in combination, have not yielded significant improvement in survival outcomes except in mismatch repair-deficient pancreatic cancer. The tumor microenvironment of pancreatic cancer has been considered as an attractive target for over a decade based on preclinical studies that suggested it may adversely affect drug delivery and antitumor immunity. In this review article, we elaborate on the biology of pancreatic cancer microenvironment, its highly complicated interaction with cancer cells, and the immune system. We also discuss plausible explanations that led to the failure of immune checkpoint inhibitors as therapeutic agents and the potential impacts of pancreatic cancer stroma on these negative studies.

Keywords

Pancreatic adenocarcinoma / durvalumab / nivolumab / ipilimumab / pembrolizumab / immune checkpoint inhibitors / immunotherapy resistance / mismatch repair deficient / microsatellite instability high / microsatellite stable / tumor-associated macrophages / myeloid-derived suppressor cells / T regs / T cells

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