Immunotherapy and Prevention of Pancreatic Cancer

Abstract

Pancreatic cancer is the third-leading cause of cancer mortality in the USA, recently surpassing breast cancer. A key component of pancreatic cancer's lethality is its acquired immune privilege, which is driven by an immunosuppressive microenvironment, poor T cell infiltration, and a low mutational burden. Although immunotherapies such as checkpoint blockade or engineered T cells have yet to demonstrate efficacy, a growing body of evidence suggests that orthogonal combinations of these and other strategies could unlock immunotherapy in pancreatic cancer. In this Review article, we discuss promising immunotherapies currently under investigation in pancreatic cancer and provide a roadmap for the development of prevention vaccines for this and other cancers.

Tumor cell–intrinsic EPHA2 suppresses antitumor immunity by regulating PTGS2 (COX-2)

“…Pancreatic ductal adenocarcinoma (PDA) is predicted to become the second leading cause of cancer-related death and is largely refractory to existing therapeutic interventions, including immunotherapies (10), primarily due to the immunosuppressive tumor microenvironment (TME) and minimal T cell infiltration in PDA (8,11,12). Importantly, we and others found that neither mutational load nor number of predicted neoantigens accounted for variation in the abundance of tumor-infiltrating T cells (9,13,14).…”

Pharmacologic activation of the G protein-coupled estrogen receptor inhibits pancreatic ductal adenocarcinoma

“…Together with our previous study on melanoma, this work raises the possibility that GPER agonists may have therapeutic utility against a wide array of GPER-expressing cancer types, and critically, may extend the utility of modern immune therapeutics to tumors, such as PDAC, that have thus far been resistant to immune therapy (25). These data highlight the importance of G protein-coupled receptor signaling in cancer, demonstrate that activation of GPER is tumor suppressive in cancers that are not classically hormone responsive, and suggest that GPER activity may contribute to biological differences between the sexes that influence cancer progression and response to modern therapies.…”

Ultrasound-Guided Orthotopic Implantation of Murine Pancreatic Ductal Adenocarcinoma

“…Pancreatic ductal adenocarcinoma (PDA) is a notoriously aggressive disease that is refractory to current treatments, with a dismal 5-year survival rate of 9% 1 . PDA recently surpassed breast cancer to become the third-leading cause of cancer-related mortality in the U.S. and is projected to become the second-leading cause (behind only lung cancer) by the year 2030 , and a dearth of T cells 5,12,13 -contribute to the failure of immunotherapies in PDA 14 . To this end, the use of a clinically-relevant animal model is an essential tool for investigating the efficacy of novel drug combinations for immunologically cold tumors in vivo.…”