# Transcriptional Regulation of Immunosuppressive Macrophages by c-Maf in Cancer

> **NIH NIH R01** · UNIVERSITY OF LOUISVILLE · 2021 · $352,275

## Abstract

Project Summary
 Immunosuppressive macrophages have been linked to cancer-related inflammation and therapeutic
resistance in cancer including chemotherapy and immunotherapy, thus representing attractive therapeutic
targets. Macrophages can be polarized into extreme M1 or M2 phenotype depending on the environmental
cues. Although macrophage phenotype within the tumor microenvironment is more complicated, it is clear
that immunosuppressive tumor-associated macrophages (TAM) phenotypically more resemble M2-like
macrophages. In the preliminary studies, we discovered that transcription factor c-Maf is highly expressed in
mouse and human polarized M2 macrophages and immunosuppressive TAM. In addition, natural product
yeast-derived particulate β-glucan treatment significantly downregulates c-Maf expression leading to
enhanced T cell responses in mice. We also demonstrated that M1 and M2 macrophages have distinct
metabolic profiles and c-Maf regulates many genes related to glycolysis. Based on these preliminary studies,
we hypothesize that transcription factor c-Maf is an essential controller and a metabolic checkpoint
for immunosuppressive TAM functional activity. Three Aims are proposed. Aim 1 determines the
cellular and molecular mechanisms by which c-Maf is regulated in immunosuppressive TAM. We will
investigate whether tumor secreted factors regulate c-Maf expression in TAM. We will also determine how
the Raf-1 kinase pathway regulates c-Maf and c-Maf-related gene expression. Finally, we will test whether
loss of function of c-Maf in TAM significantly delays tumor progression and metastasis. Aim 2 determines
which TAM metabolic pathway(s) is regulated by c-Maf using systems metabolomics approach. We will first
determine TAM metabolic pathways using Stable Isotope Resolved Metabolomics (SIRM) approach.
Furthermore, we will determine which metabolic pathways are regulated by c-Maf. Finally we will determine
the causative role of metabolic reprogramming in β-glucan-mediated TAM functional conversion. Aim 3
determines whether the dectin-1 agonist β-glucan modulates TAM function of human non-small cell lung
cancer (NSCLC) via the c-Maf pathway. We will determine whether β-glucan treatment downregulates c-
Maf expression and alters c-Maf-regulated genes in human NSCLC TAM. We will also determine whether
human TAM functions are reversed upon β-glucan treatment. Finally, we will examine whether β-glucan
treatment in patients with NSCLC downregulates c-Maf expression and alters monocyte suppressive
function. The overall goal of this proposal is to understand the transcriptional regulation of
immunosuppressive TAM by c-Maf and establish the transcription factor c-Maf as a novel target for human
cancer immunotherapy.

## Key facts

- **NIH application ID:** 10115632
- **Project number:** 5R01CA213990-05
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** JUN YAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $352,275
- **Award type:** 5
- **Project period:** 2017-02-06 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10115632

## Citation

> US National Institutes of Health, RePORTER application 10115632, Transcriptional Regulation of Immunosuppressive Macrophages by c-Maf in Cancer (5R01CA213990-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10115632. Licensed CC0.

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