Divergent Roles of MerTK,Tyro3, and Axl in Pancreatic Cancer and Metastasis

Abstract public domain (NIH RePORTER)

ABSTRACT Pancreatic Ductal Adenocarcinoma (PDAC) is perhaps the most recalcitrant human neoplasm. With 10% overall 5-year survival and an increasing incidence, PDAC will be the second leading cause of cancer deaths within a decade. The constellation of chemo- and targeted therapy resistant tumor cells, and a tumor microenvironment featuring suppressive innate immune cells and fibroblasts frustrates therapeutic success. PDAC and preclinical PDAC models both show a massive myeloid and fibroblast cell infiltration which suppresses effector T cells and promotes metastases. Our data implicate a family of receptor tyrosine kinases Tyro3, Axl, MerTK (TAM RTKs) in directing pro-tumorigenic polarization of CAFs and myeloid cells in PDAC. The homeostatic role of myeloid cell TAM RTKs is to coordinate suppression of innate immune inflammatory responses to apoptotic material preventing chronic inflammation and autoimmunity. Our preliminary data, show that TAM RTKs play non- redundant and sometimes opposing functions in the PDAC tumor microenvironment (TME), leading to polarization of myeloid cells and fibroblasts. Clinical trials of TAM RTK inhibition are beginning; thus, our work to understand the consequences and mechanism of inhibition for each TAM RTK is both timely and significant. Host MerTK and Tyro3 in wild type mice promote PDAC growth and contribute to lack of responsiveness to anti- PD1 therapy, as germline MerTK or Tyro3 deletion slow PDAC growth, markedly reduces liver metastasis, and promotes anti-PD-1 efficacy. However, in the Axl-/- mice there is an unexpected increase in metastatic outgrowth. Our group has synthesized orally bioavailable, selective MerTK kinase inhibitors, which recapitulate aspects of MerTK and/or Tyro3 genetic loss. Lastly our preliminary studies in patients identify MerTK+ and Tyro3+ myeloid cells and document an increase in MerTK+/Tyro3+ MDSCs in the blood of PDAC patients. Hypothesis. MerTK+ and/or Tyro3+ monocytes, macrophages, MDSCs, and Tyro3+ fibroblasts are expanded in PDAC, and have at least some separate roles in the suppressive TME and metastasis promotion. Our Specific Aims are: Aim 1: To determine how MerTK and Tyro3 act in the innate immune compartment to accelerate PDAC growth and metastasis and how Axl has the opposite effect. Aim 2: To determine the role of Tyro3 in PDAC cancer associated fibroblasts and Aim 3: To evaluate the therapeutic potential of targeting TAM RTKs in PDAC in preclinical PDAC models (using UNC inhibitors one of which is in Phase 1 trials) in combination with other cytotoxic and immune therapies. We will quantify, functionally characterize, and study gene expression signature of MerTK+ and Tyro3+ myeloid cells in the circulation, tumors and lymph nodes and fibroblast cells in the PDAC patient tumors before and during therapy. Success would represent a significant advance toward understanding how to make immunologically “cold” PDAC tumors “hot” and responsive to immunotherapy.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE The dismal outcomes of pancreatic cancer and its unresponsiveness to immunotherapy is, in part, due to the pro-tumorigenic, immunosuppressive tumor microenvironment engendered by infiltrating myeloid and fibroblastic cells. We have identified MerTK, Tyro3 and Axl receptor tyrosine kinases as important but distinct regulators of immunosuppressive myeloid cells and potentially cancer-associated fibroblasts. This research will elucidate mechanisms by which these kinases hinder the immune response and will evaluate novel, clinically applicable therapeutic agents that could magnify the response to current immunotherapies.