# Targeting ROS enzymes in immunosuppressive myeloid cells to enhance immunotherapy

> **NIH NIH P20** · WEST VIRGINIA UNIVERSITY · 2024 · $260,435

## Abstract

PROJECT SUMMARY – Targeting ROS enzymes in immunosuppressive myeloid cells to enhance
immunotherapy
Although immune checkpoint therapy (ICT) has demonstrated long term survival for a subset of patients suffering
from metastatic melanoma, the majority of patients do not respond. The limited success of ICT has, in large part,
been due to the presence of a highly immunosuppressive tumor microenvironment. Immunosuppressive myeloid
cells (IMCs) are critical drivers of this immunosuppressive microenvironment, promoting tumor growth and
evasion of the immune system. A major challenge in the identification of these IMCs is that the current phenotypic
criteria using surface markers to characterize them overlaps with that used for myeloid cells, including neutrophils
and monocytes, thus, distinguishing this immunosuppressive subset of innate immune cells will be dependent
upon functional characterization. The immunosuppressive nature of IMCs is known to depend upon reactive
oxygen species (ROS). In these IMCs, the respiratory burst pathway is a major source of ROS which is primarily
produced by the enzymes myeloperoxidase (MPO) and NADPH oxidase 2 (NOX2). Thus, MPO and NOX2 may
be important regulators of the immunosuppressive function of IMCs. However, little is known with regards to the
contribution of immunosuppressive IMCs, particularly the function of ROS producing MPO and NOX2 enzymes,
in melanoma immunotherapy response and disease progression. The long-term goal of this research project is
to understand the molecular mechanisms responsible for the function and accumulation of IMCs during
melanoma progression. The overall objective of this proposal is to understand the contribution of the respiratory
burst enzymes to the immunosuppressive function of IMCs. The central hypothesis is that increased MPO
and NOX2 activity contributes to IMC immunosuppression where inhibition of these respiratory burst
enzymes decreases IMC immunosuppressive function enhancing ICT efficacy and prolonging survival.
The proposed aims of 1. Evaluate the contribution of respiratory burst enzymes regulating melanoma ICT
response, 2. Identify IMCs interactions during melanoma ICT response, and 3. Evaluate the presence of
respiratory burst enzymes pathological samples of melanoma, will be conducted using murine preclinical models
and pathological samples to explore the changes in the respiratory burst enzymes. In addition, these studies will
utilize specific inhibitors Verdiperstat, AZD5904 and histamine dihydrochloride for MPO and NOX2, respectively;
these inhibitors are under evaluation in Phase 3 trials for neurodegenerative disorders and leukemia. We
recognize these inhibitors have not yet been utilized in cancer treatments in the clinical setting; these preclinical
studies will provide much needed understanding of basic mechanisms for the translation of their use with
immunotherapy for cancer. These studies will be the first to characterize the role of respiratory burst enzy...

## Key facts

- **NIH application ID:** 10916378
- **Project number:** 5P20GM121322-07
- **Recipient organization:** WEST VIRGINIA UNIVERSITY
- **Principal Investigator:** TRACY W LIU
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $260,435
- **Award type:** 5
- **Project period:** 2018-08-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10916378

## Citation

> US National Institutes of Health, RePORTER application 10916378, Targeting ROS enzymes in immunosuppressive myeloid cells to enhance immunotherapy (5P20GM121322-07). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10916378. Licensed CC0.

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