Our primary hypothesis is that the efferocytosis receptor MerTK facilitates immune evasion and subverts T cell-mediated clearance in acute myeloid leukemia (AML). MerTK is expressed on macrophages and dendritic cells (antigen presenting cells, APCs) where it carries out efferocytosis ? the process of non-immunogenic removal of apoptotic cellular debris through secretion of T cell suppressive cytokines (IL-10, TGF-?) and tolerogenic antigen presentation. Due to increased apoptotic debris in leukemia (from rapid cell turn over), the underlying premise of our research is that efferocytosis is tu-mor-permissive and drives immunological tolerance. Our previous research showing MerTK expression on >80% of AML patient samples and that inhibition of MerTK caused cell death, led to the development MerTK tyrosine kinase inhibitors (TKIs) that will soon be evaluated in early phase clinical trials. Given MerTK expression on APCs, we recently hypothe-sized that MerTK inhibition might mitigate the immunosuppressive and tolerogenic leukemia microenvironment, and im-prove leukemia-specific T cell responses. To evaluate this, we administered an orally active MerTKI in a syngeneic immunocompetent murine AML model and found that T cell activity is necessary for maximal efficacy, though T cells do not express MerTK. Our preliminary data also demonstrated that MerTK inhibition directly altered APC function and also had broad downstream effects on T cells, likely through secretion of immunomodulatory cytokines and altered checkpoint ligand and receptor expression. Similar results were also found on MerTK-expressing AML cells when cultured in vitro with MerTKIs. These results demonstrate that MerTK inhibition alters the microenvironment from tumor-permissive to-ward conditions which augment immune responsiveness to leukemia. In this proposal, we will rigorously investigate the mechanisms by which inhibition of MerTK (on APCs and AML cells) can improve T cell-mediated AML clearance using genetic models of MerTK knockout and clinical candidate MerTKIs. Though Dr. Lee Sherick has a strong research base in experimental therapeutics, this proposal provides the cancer immunology experimental skills and knowledge base needed for her transition to an independent investigator in cancer immuno-therapeutics.
The specific aims assess whether: 1) inhibition of APC MerTK signaling augments leukemia-specific T cell responses to AML, and 2) MerTK inhibition on AML cells decreases immune evasion. Her mentorship team consists of recognized leaders in cellular therapy, acute mye-loid leukemia, and innate/adaptive immune interactions, including Dr. Michael Verneris (primary mentor), Craig Jordan (co-mentor), and Ross Kedl (co-mentor), through which Dr. Lee Sherick will receive training in immune signaling (T cell contact dependent and independent) in the context of leukemia, immune dysfunction in malignancy, and development of novel clinically relevant immunotherapeutic approaches. The career development plan clearly outlines how Dr. Lee Sherick will achieve these goals by building upon her previous research using the proposed research aims, didactic course-work, attendance at local and national meeting, and guidance from her mentorship team and scholarly oversight committee. The proposed research and associated career development plan have been designed specifically to facilitate her transition to independent investigator with the long-term goal of developing additional novel and innovative therapeutics to in-crease anti-leukemia immunity.
The proposed research aims to investigate new ways to improve anti-cancer immunity by inhibiting the tumor- permissive process called efferocytosis by tumor-associated macrophages and dendritic cells. This research is relevant to public health given that it may provide additional understanding of immunologic dysfunction in cancer, as well as provide a po-tential therapeutic approach for a wide variety of cancers.