# MerTK and the Innate Immune Response to Melanoma

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $347,700

## Abstract

The TAM family (Tyro3, Axl and MerTK) of receptor tyrosine kinases (RTKs) was one of the last families
identified and one of the last to evolve. Their principal role in multicellular organisms appears to be detection of
phosphatidyl serine (PtdSer) through a linking protein ligand (e.g. Gas6 or ProS) that together bind to and
activate MerTK and intracellular signaling. PtdSer is exposed on the surface of aggregating platelets,
exosomes and most prominently on the external surface of billions of cells that daily undergo apoptosis. The
best studied homeostatic function of the family is the macrophage role of MerTK as it responds to apoptotic
PtdSer by triggering ingestion (effercytosis) and signaling that this is “self-material”. This signal prevents an
inflammatory macrophage response (e.g. IL-12) and polarizes the macrophage to an M2-like (e.g. IL-10,
TGFb), wound healing, alternatively activated phenotype. This MerTK action is crucial for preventing
autoimmunity efficiently ingesting dying cells and clearing self-antigens; this MerTK action is deleterious and
immunosuppressive in tumor microenvironment (TME) and its innate immune infiltrate. TME
immunosuppressive activities are stimulated by MerTK alone or in combination with Axl and Tyro 3 signaling in
the innate immune cell repertoire. For example, our new data shows that all three TAM RTKs are present in
Myeloid Derived Suppressor Cells and each (MerTK, Axl and Tyro 3) enhances MDSC suppressive action.
MerTK activation also is key in the suppression of cross presentation by the tolerizing dendritic cell in which
MerTK is substantially upregulated.
In metastatic melanoma, immune checkpoint therapy has produced remarkable responses, some of which are
durable. However, patients without an M1, Th1 immune infiltrate are less likely to benefit. Our overall
hypothesis is that MerTK, Axl and Tyro 3 are in part responsible for the counterproductive, immunosuppressive
immune infiltrate in melanoma (and other tumor types) through their innate immune cell action. This TAM RTK
immunosuppressive action is probably present in most TMEs which are characterized by hypoxia, abundant
apoptotic cells, and presence of secreted paracrine and autocrine TAM ligands (Gas6 and ProS). Our
objective is to characterize the MerTK (and Axl, Tyro 3) signals in MDSCs, macrophages monocytes and
tolerizing DCs, their downstream mechanisms and their consequences for the adaptive T reg and T eff cell
responses. We will use wild type and knockout mice with preclinical syngeneic and genetically-engineered
mouse melanomas as our models. We have UNC synthesized small molecule MerTK (and newer UNC TAM
RTK) inhibitors as well as genetic methods to determine if inhibition of MerTK and other TAM receptors can
produce an immune-modulatory tumor response. We will also test whether the combinations of immune
checkpoint antibodies (anti-CTLA4 and anti-PD-1) and TAM RTK inhibitors will increase therapeutic efficacy.

## Key facts

- **NIH application ID:** 9852884
- **Project number:** 5R01CA205398-04
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** H. Shelton Earp
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $347,700
- **Award type:** 5
- **Project period:** 2017-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852884

## Citation

> US National Institutes of Health, RePORTER application 9852884, MerTK and the Innate Immune Response to Melanoma (5R01CA205398-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9852884. Licensed CC0.

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