# ALDH Inhibition as Modulator of Tumor Immunobiology

> **NIH NIH R01** · MAGEE-WOMEN'S RES INST AND FOUNDATION · 2021 · $60,414

## Abstract

Despite small improvements to standard of care protocols, the overall survival of patients with ovarian cancer
(OvCa) has not significantly changed for several decades. There is a clear unmet clinical need to develop new
therapies for this highly aggressive disease ranking 5th in cancer deaths in women, with the 3rd highest mortality
to incidence ratio of all cancers. Aldehyde dehydrogenase-1A enzymes (ALDH1A) represent a therapeutic target
for OvCa. ALDH1A enzymes are upregulated in ovarian cancer initiating cells where they mediate the
biosynthesis of retinoic acid (RA), to regulate numerous cellular processes. We recently demonstrated that
inhibition of ALDH1A (ALDHi) can have a dual effect: it can directly target tumor cells to slow proliferation and
act on immune cells to enhance proliferative response of both dendritic cells (DC) and CD8+ T cells. Our
overarching hypothesis is that ALDHi can act as an immune modulator (via individual RA receptors
RAR/RXR and NR4A1 co-receptor) and can be used to enhance immunotherapeutic approaches in OvCa.
To test this hypothesis, our five-year project R01CA238315, the parent grant to this Research Supplement to
Promote Diversity in Health-Related Research, proposes three specific aims (SA) SA1: To identify the RA
receptors and downstream factors that drive ALDHi induced necrosis in tumor cells and to determine whether
ALDHi-induced CIC necroptosis is inflammatory cell death. SA2: Assess the impact of ALDHi on host DC and T
cells. SA3: To determine the ability of ALDHi to enhance immunotherapy in OvCa. The current, one-year project
builds on our new findings showing that, in addition to their immune promoting function in DCs and CD8 T cells,
ALDHi also lower the frequency of tumor associated macrophages (TAM), a critically important immune cell
subset with immune suppressive, tumor-promoting function. The goal of the current one-year proposal is to
extend our studies (originally focused on DC and T cells) to (1) identify the mechanisms of ALDHi induced effects
on TAM and (2) elucidate the downstream consequences of these ALDHi effects on modulating the tumor
microenvironment and enhancing immune therapy response. To achieve this, we will use primary macrophages
derived ex vivo from blood (human) or bone marrow precursors (mice) and matured under M1/M2 inducing
conditions in the presence or absence of ALDHi. NR4A1 involvement will be dissected using bone marrow
precursors from NR4A1 reporter mice and target specificity will be confirmed in NR4A1 null mice. The immune
modulatory roles of TAM will be further dissected in vivo, in NR4A1 mice challenged orthotopically with ovarian
tumors and treated with ALDHi or vehicle control.
IMPACT: This project is in line with the NIH mission to promote diversity among investigators doing research in
health-related sciences. The studies proposed here will define new roles for a ALDHi in immunotherapy in OvCa.
Given ALDH is broadly linked with therapeutic resistance in can...

## Key facts

- **NIH application ID:** 10380368
- **Project number:** 3R01CA238315-02S1
- **Recipient organization:** MAGEE-WOMEN'S RES INST AND FOUNDATION
- **Principal Investigator:** Ronald J Buckanovich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $60,414
- **Award type:** 3
- **Project period:** 2020-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10380368

## Citation

> US National Institutes of Health, RePORTER application 10380368, ALDH Inhibition as Modulator of Tumor Immunobiology (3R01CA238315-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10380368. Licensed CC0.

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