Targeting the liver for immunotherapy in pancreatic cancer

Abstract public domain (NIH RePORTER)

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.

Public health relevance public domain (NIH RePORTER)

Project Narrative T cell immunotherapy has yet to produce clinical benefit for most patients with pancreatic cancer. In this proposal, we investigate (i) mechanisms of primary resistance to immunotherapy with a focus on the liver as a known immunoregulatory organ and (ii) therapeutic implications of the liver in shaping cancer immunogenicity and the efficacy of immunotherapy. The proposed studies will use clinically relevant mouse models of cancer and human tissues to inform the design of novel strategies to broaden the efficacy of cancer immunotherapy.