# Targeting MerTK as an immunotherapeutic strategy in acute myeloid leukemia

> **NIH NIH K08** · UNIVERSITY OF COLORADO DENVER · 2022 · $175,285

## Abstract

Abstract
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-β) 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 approache...

## Key facts

- **NIH application ID:** 10439596
- **Project number:** 5K08CA222699-05
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Alisa Lee Sherick
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $175,285
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10439596

## Citation

> US National Institutes of Health, RePORTER application 10439596, Targeting MerTK as an immunotherapeutic strategy in acute myeloid leukemia (5K08CA222699-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10439596. Licensed CC0.

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