Cold Pancreatic Cancer? Not so much anymore!

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The asymptomatic nature of pancreatic cancer results in a five-year survival rate of 6 percent [1], the worst among cancers. With extremely moderate advances in the treatment for the disease, it is projected that by 2030, pancreatic cancer will be among the leading causes of death for both men and women [2].

Over the past few years, immunotherapy has provided substantial relief to previously incurable metastatic cancers. For example, metastatic melanoma, which previously had an average life expectancy between six to 12 months, now has a three-year survival rate that tops 50 percent in some studies due to the implementation of immune checkpoint blockade as the standard of care first-line treatment [3]. While immunotherapy in the form of immune checkpoint blockade, and now vaccines and adoptive T Cell transfer, has revolutionized patient care for a number of disorders, immunotherapy remains largely ineffective against pancreatic cancer [4][5].

The ineffectiveness of immunotherapy in pancreatic cancer can be attributed to its “immune-cold” nature. There are a number of factors contributing to the ability of pancreatic cancer to remain largely unresponsive to immunotherapy. The anti-tumor immune response is highly dependent on antigenicity: the ability of tumor cells to form new and distinct proteins that our immune system can recognize as foreign, of the tumor. Unlike melanoma and lung cancer, pancreatic cancer has an extremely poor antigenicity [6]. However, it is well documented that our immune system can recognize pancreatic cancer cells suggesting the presence of more complex mechanisms through which pancreatic cancer builds defenses against our immune system.

Recognition of pancreatic cancer cells by our immune system is largely hindered by the presence of a largely immunosuppressive tumor microenvironment, which is characterized by a dense stroma and pro-tumoral immune and stromal cells [7][8]. Tumor cells are surrounded by fibrous tissue that contains cancer-associated fibroblasts, blood vessel endothelial cells and immunosuppressive immune cells. The stroma leaves anti-tumor lymphocytes tumor-excluded or unable to get in direct contact with tumor cells and trapped by the dense tissue surrounding the tumor cells [9]. Importantly, cells like alternatively activated macrophages and regulatory T Cells constitute the majority of infiltrated immune cells in the tumor microenvironment. The immunosuppressive immune cells present in the stroma help secrete factors that promote the formation of the fibrous stroma, promote the formation of new blood vessels that tumors exploit to obtain resources, enable the growth and progression of tumors and, importantly, dampen the immune response against the tumor. The density of the stroma also impairs the flow of oxygen which results in hypoxia and an acidic environment that prevents the infiltration of anti-tumor immune cells. The physical and chemical barriers posed by the tumor stroma ultimately results in a “cold” immune environment. With the clear importance of the pancreatic cancer stroma in protecting tumor cells from our body’s defenses, one of the biggest questions plaguing scientists is whether we can deplete this stroma to improve delivery of therapeutics and facilitate the infiltration of immune cells into the tumor microenvironment.

A lot of research on ameliorating pancreatic cancer outcomes is conducted right here in Washington University in St. Louis. Specifically, Dr. David DeNardo in the Washington University School of Medicine is actively searching for ways to mitigate the effects of the pancreatic cancer stroma. DeNardo has developed a track record in mounting significant responses to immunotherapy in mice models of pancreatic cancer, which like humans, historically do not respond to immunotherapy. His lab accomplishes this by targeting elements of the pancreatic stroma to unleash the immune response against pancreatic cancer. Using innovative strategies, DeNardo’s lab has developed techniques to target fibrosis around tumors, a highly immunosuppressive cell immune cell type known as myeloid derived suppressor cells, tumor-associated macrophages and dendritic cells. One prominent therapeutic target identified is the Focal Adhesion Kinase (FAK). In their 2016 Nature Medicine paper, they describe the benefits in using FAK inhibitors in combination with immunotherapy for pancreatic cancer [10]. The use of FAK inhibitors resulted in significant reduction in tumor size due to reduction in fibrosis, reduction in infiltration of immunosuppressive cells and increased infiltration of anti-tumor immune cells, particularly cytotoxic T Cells. More importantly, the use of FAK inhibitors rendered the previously unresponsive pancreatic cancer models responsive to immunotherapy. This discovery has manifested in a Phase 1 clinical trial that is projected to be completed in July 2020. DeNardo lab has identified numerous targets, like FAK, that can be exploited to target components of the dense to render pancreatic cancer responsive to immunotherapy [10][11].

Innovative techniques to overcome the barrier posed by the tumor stroma are the future of pancreatic cancer treatment. Such therapeutics not only improve the efficacy of immunotherapy but can also help minimize doses and improve delivery of other therapeutic agents like chemotherapy. Work done by scientists like DeNardo are actively helping improve outcomes for pancreatic cancer patients by turning the previously cold tumors hot.

Written by: Madhav Subramanian
Edited by: Anhthi Luong




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