# Regulation of antigen presenting cells in the tumor microenvironment by retinoic acid

> **NIH NIH R37** · UNIVERSITY OF PENNSYLVANIA · 2024 · $353,132

## Abstract

Project Summary and Abstract
Evading immune responses is a hallmark of cancer. Solid tumors create a microenvironment that prevent
detection of tumor cells by the immune system and block anti-tumor T cell activity. The therapeutic value of
targeting immune evasion pathways is highlighted by the recent clinical successes of alleviating T cell
suppression via immune checkpoint blockade in a handful of solid tumors. However, anti-tumor T cells are not
generated in most solid tumors, which greatly limits the application of checkpoint blockade. One reason for this
is the paucity and dysfunction of antigen-presenting dendritic cells (APCs) in solid tumor microenvironment
(TME), but the underlying pathways are poorly understood. Our long-term goal is to discover and delineate
pathways that control APC recruitment, differentiation, and function in TME. The overarching goal is to target
these pathways to enhance antigen presentation and adaptive immune responses for solid tumor
immunotherapy. I have previously developed powerful genetically engineered mouse models of sarcomas, a
type of lethal solid tumor, as well as murine models to study antigen-presenting cells. Using these tools, we
have recently discovered that retinoic acid (RA) produced by tumor cells act on tumor-infiltrating monocytes to
prevent their differential into dendritic cells, instead promoting their differentiation into immunosuppressive
macrophages. Furthermore, we have found that the cytokine IL13 promotes RA production in tumor cells.
Based on these findings, our central hypothesis is that IL13-induced RA production by tumor cells prevents the
generation of monocyte-derived dendritic cells in TME. Our three specific aims will; delineate the mechanism
by which RA affects monocyte differentiation and antigen presentation (Aim 1), uncover the source of IL13 in
TME and its impact on anti-tumor immune responses (Aim 2), and examine the potential of targeting IL13 and
RA signaling for tumor immunotherapy (Aim 3). This work will have significant impact on our understanding of
immunomodulation in solid tumors and extend our understanding of how tissue metabolites can control
monocyte differentiation. Our findings will also open new avenues for solid tumor immunotherapy based on
targeting RA signaling and APCs. The clinical implications are particularly impactful for sarcomas where
current treatment options are extremely limited. Our work is innovative because it will open new avenues of
research examining the role of retinoid signaling in APC differentiation and tumor immunity. There are many
commercially available small molecule inhibitors of RA signaling, but none has been used for therapeutic
purposes. Therefore, our work will not only provide a proof of concept for RA blockade in tumor
immunotherapy, but is also amenable to rapid human translation.

## Key facts

- **NIH application ID:** 10656950
- **Project number:** 4R37CA234027-06
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Malay Haldar
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $353,132
- **Award type:** 4N
- **Project period:** 2018-12-03 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10656950

## Citation

> US National Institutes of Health, RePORTER application 10656950, Regulation of antigen presenting cells in the tumor microenvironment by retinoic acid (4R37CA234027-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10656950. Licensed CC0.

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