# Enhanced Immunotherapy by Targeting the Pros1:Macrophage Mer Axis

> **NIH NIH K22** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2022 · $192,352

## Abstract

PROJECT SUMMARY/ABSTRACT
 Tumors can utilize mechanisms of normal physiological immune regulation to suppress the tumor-specific
immune response. Targeted immunotherapies directed against immune checkpoints, like PD-1/PD-L1 and
CTLA4, have improved patient outcomes but are only effective in a subset of cancers. The durable responses
of some patients, resulting from checkpoint-targeted therapy, has sparked great interest in identifying and
targeting other innate and adaptive immune checkpoints.
 Recent studies have identified the Tyro3/Axl/Mer (TAM) family of receptor tyrosine kinases as a novel
innate immune checkpoint. Ubil et al. (JCI, 2018) show that tumors secrete Pros1, a Tyro3/Mer ligand, which
suppresses the pro-inflammatory M1 response of host macrophages. Pros1 binding induces the recruitment of
p38 and PTP1b to Mer, preventing nuclear translocation of p38 and subsequent expression of M1 associated
genes. Genetic deletion of macrophage Mer or PTP1b restores M1 polarization in the presence of Pros1.
 By targeting Pros1:macrophage Mer signaling it may be possible to enhance cancer
immunotherapy. To better understand and prevent Mer mediated immune suppression the following specific
aims are proposed: 1) Determine the roles of Mer kinase activity and adapter protein recruitment in M1
suppression, 2) Identify the basis for variable immune suppression by Pros1 secreting tumors and 3) Ascertain
whether PTP1b inhibition as mono- or combination therapy can increase intra-tumoral immune infiltrate and
improve survival.
 To establish the importance of Mer kinase activity, CRISPR will be used to genetically ablate the Mer ATP
binding site and RNAseq used to monitor global transcriptional changes during Pros1 induced M1 suppression.
Bioinformatics analysis will identify key pathways affected by Mer kinase, which will be validated biochemically.
Immunoprecipitation and proteomic analysis will be used to determine the importance of Pros1-induced
dynamic adapter protein recruitment and novel protein:protein associations. Subtle genetic alterations can lead
to reduced Pros1 protein activity. Changes in tumor Pros1 sequence will be correlated with ability to suppress
M1 polarization and a predictive model constructed to identify which tumors will be susceptible to Pros1:Mer
targeted therapy. Efficacy of pharmacological PTP1b inhibition (mono- and combination therapy) to increase
tumor immune infiltrate and survival will be determined in primary and metastatic tumor models.
 Together, the proposed study may identify novel therapeutic targets to prevent Pros1:Mer mediated
immune suppression, yield predictive criteria as to which patients may benefit from Pros1:Mer targeted therapy
and whether pharmacological PTP1b inhibition is a viable strategy to improve the immune response to cancer.

## Key facts

- **NIH application ID:** 10304878
- **Project number:** 5K22CA237742-03
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Eric S Ubil
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $192,352
- **Award type:** 5
- **Project period:** 2019-12-09 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10304878

## Citation

> US National Institutes of Health, RePORTER application 10304878, Enhanced Immunotherapy by Targeting the Pros1:Macrophage Mer Axis (5K22CA237742-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10304878. Licensed CC0.

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