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

> **NIH NIH R37** · UNIVERSITY OF PENNSYLVANIA · 2021 · $368,288

## Abstract

Project Summary
Evading immune responses is a hallmark of cancer. The `tumor-immunity cycle' begins with the processing of
tumor-associated proteins by dendritic cells (DC), which initiate a T-cell response in draining lymph nodes,
followed by the trafficking of these anti-tumor T cells into the tumor to mediate tumor lysis. Tumors can block
one or more steps of this cycle to evade immune responses. The therapeutic potential of targeting such
immune-evasion pathways is highlighted by the clinical success of immune checkpoint inhibitors that alleviates
T cell suppression in cancer. However, tumor-reactive T cells are not generated in most solid tumors, which
limit the utility of immune checkpoint inhibitors. A major reason for this failure to generate anti-tumor T cells is
the paucity and dysfunction of DCs in the tumor microenvironment (TME). While DCs are rare inside tumors, a
closely related cell type, macrophages, are abundant. In contrast to DCs, tumor-associated macrophages
(TAMs) are immunosuppressive and promote tumor progression. Both DCs and TAMs can originate from
monocytes but there is a major knowledge gap in our understanding of why monocytes preferentially
differentiate into immunosuppressive TAMs but not immunostimulatory DCs in solid tumors. Our long-term
interest is to understand the development and differentiation of macrophages and DCs in the TME with the
overarching goal of targeting these cells for cancer immunotherapy. I previously developed powerful
genetically engineered mouse models of sarcomas, a type of lethal solid tumor, as well as mouse models to
study antigen-presenting cells. Using these tools in my laboratory, I recently discovered that tumor cell-derived
retinoic acid blocks DC but promotes TAM differentiation from monocytes. Furthermore, I 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 immunostimulatory DCs from TME
monocytes. I posit that this is a major pathway of immune evasion in solid tumors. Our two specific aims will
delineate the mechanism by which RA affects monocyte differentiation and antigen presentation (Aim 1) and
uncover how IL13 controls RA production in TME (Aim 2). We will also examine the value of targeting this
pathway for tumor immunotherapy. This work will have significant impact on our understanding of
immunomodulation in solid tumors and establish a new approach in solid tumor immunotherapy based on
targeting RA signaling in APCs. Our work is innovative because it will open new avenues of research into the
role of retinoid signaling in APC differentiation and tumor immunity.

## Key facts

- **NIH application ID:** 10051410
- **Project number:** 5R37CA234027-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Malay Haldar
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $368,288
- **Award type:** 5
- **Project period:** 2018-12-03 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10051410

## Citation

> US National Institutes of Health, RePORTER application 10051410, Regulation of antigen presenting cells in the tumor microenvironment by retinoic acid (5R37CA234027-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10051410. Licensed CC0.

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