Targeting the liver for immunotherapy in pancreatic cancer

Project Summary
Immunotherapy has shown the capacity to improve outcomes for some patients across a wide-range of
malignancies. However, many patients still do not achieve clinical benefit and in particular, patients with liver
metastases demonstrate poor responsiveness to immunotherapy. Emerging evidence suggest a role for the liver
in determining outcomes with cancer immunotherapy. To this end, the liver is a critical determinant of immune
regulation and plays a central role in T cell peripheral tolerance. Yet, how the liver may regulate immunotherapy
efficacy is unclear. This represents a significant gap in our knowledge that has strong translational implications.
In gastrointestinal malignancies, the liver may be continuously exposed to malignant cells as well as soluble
factors and antigens released by primary tumors. We hypothesize that this connection between the gut and liver
may have significant implications on T cell immunosurveillance in cancer. In support of this hypothesis, we have
found that primary tumors release soluble factors that activate hepatocytes in the liver. This process can begin
during the earliest stages of cancer development. Activated hepatocytes respond by releasing acute phase
reactants which act to orchestrate an immunological niche environment in the liver that is underpinned by the
recruitment of neutrophils and myeloid cells and the deposition of extracellular matrix proteins. In the setting of
hepatocyte activation, primary tumor development, occurring in the pancreas, demonstrates poor T cell
infiltration. However, genetic blockade of hepatocyte activation converts a T cell “cold” tumor into a “hot” tumor.
This finding underscores the importance of the liver in regulating T cell immunosurveillance in cancer. Our priority
is to decipher mechanisms by which the liver regulates T cell immunosurveillance in cancer and to understand
its implications in regulating the efficacy of cancer immunotherapy. Therefore, in Aim 1, we will define
mechanisms by which hepatocytes direct tumor immune evasion with a focus on signaling pathways regulated
by hepatocytes and their impact on T cell priming and trafficking. In Aim 2, we will investigate the impact of
hepatocyte activation on the immunobiology of PDAC and the efficacy of cancer immunotherapy. Together, these
complementary aims will inform the development of novel treatment paradigms designed to curtail the
immunosuppressive effects of liver inflammation as a strategy to broaden the efficacy of cancer immunotherapy.

Grant Number: 5R01CA197916-09
NIH Institute/Center: NIH
Principal Investigator: Gregory Beatty