Targeting a phosphatidylserine/TAM receptor/PD-L1 axis as a vulnerability in cancer

Project Summary:
Tyro3, Axl, and Mertk (abbreviated TAM receptors) are a family of homologous type I Receptor
Tyrosine Kinases (RTKs) that have homeostatic functions under physiological conditions to
dampen inflammation and maintain tissue tolerance in multi-cellular organisms. The ligands for
TAMs are two vitamin K- modified proteins, Growth arrest specific factor 6 (Gas6) and Protein S
(Pros1) that bind phosphatidylserine (PS) on apoptotic cells, and in doing so, act as bridging
molecules to facilitate the clearance of apoptotic cells (efferocytosis). While PS-mediated
efferocytosis, most emblematically via Mertk expressed on macrophages, have important
homeostatic functions to prevent chronic inflammation and autoimmunity, the constitutively
externalized PS that occurs in the tumor microenvironment (TME) of solid cancers, in combination
with the expression of Mertk on infiltrating macrophages, patho-physiologically subvert PS-
mediated tolerogenic functions to suppress host anti- tumor immune responses. The central
hypothesis in this application is that constitutively dys- regulated PS externalization
observed in the TME, in combination with the infiltration of Mertk-expressing
macrophages, act as an important immune inhibitory axis to suppress host anti- tumor
immunity. This axis is likely to be activated in a wide range of solid cancers for immune escape,
but also may represent vulnerability in cancer if effectively targeted by therapeutics. In this
application, we outline mechanistic experiments to identify how externalized PS is dysregulated
in the TME (aim #1) as well as determine the mechanisms by which Mertk acts as an inhibitory
receptor on macrophages to suppress host anti-tumor immunity and tolerance (aim #2). In aim
#3, we propose a series of pre-clinical therapeutic mouse studies to test combinations of a first-
in-class anti-Mertk neutralizing mAb in combination with anti-PD1 mAb, as well as explore and
validate the biology of Mertk as an inhibitory receptor using human models. Collectively, our
studies aim to open up new avenues to interrogate a novel type of checkpoint inhibitory network
in immuno-oncology.

Grant Number: 5R01CA260137-05
NIH Institute/Center: NIH
Principal Investigator: Raymond Birge