Journal article
Neovascular pruning by IDO1 inhibitors can potentiate immunogenic cytotoxicity of ischemia-targeted agents to synergistically enhance anti-PD-1 responsiveness
Journal for immunotherapy of cancer, v 13(5), 011398
30 May 2025
PMID: 40447318
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Background Strategies for deploying indoleamine 2,3-dioxygenase 1 (IDO1)-targeted therapies for use against cancer have focused on IDO1's role in promoting peripheral immune tolerance that shields tumors from effector T cells. However, preclinical investigation of both primary and metastatic tumor development in the lungs has uncovered a previously unappreciated role for IDO1 in directing a counterregulatory response to interferon (IFN)-gamma that realigns the local inflammatory environment to promote tumor neovascularization. Understanding how to therapeutically leverage the ability of IDO1 inhibitors to subvert inflammatory neovascularization within the tumor microenvironment has potential ramifications for future clinical development of these compounds.Methods Pulmonary metastases seeded by orthotopically implanted 4T1 breast carcinoma cells were evaluated by confocal microscopy for the impact of both genetic and pharmacological IDO1 inhibition, alone or in combination with ischemia-directed cytotoxic agents, on markers of blood vessel density, hypoxia and cell death. Tumor immunogenicity and programmed death-ligand 1 (PD-L1) elevation were also evaluated. Quantitative analysis of these results was used to guide combinatorial treatment regimen development.Results Inhibiting IDO1 activity resulted in reduced neovascular density and elevated hypoxia in pulmonary metastases for which host IFN-gamma was essential while adaptive immunity was dispensable. The tumors were consequently sensitized to the cytotoxic activity of ischemia-targeted agents including the protein kinase R-like endoplasmic reticulum kinase (PERK) inhibitor GSK2656157, the dithiol oxidative antimetabolite TTL-315, and the hypoxia-activated prodrug evofosfamide. Evofosfamide provoked the greatest degree of immunogenic cell death, while hypoxia, among other stressors, induced PD-L1. Based on this information, synergistic improvement in median survival was demonstrated in mice with established lung metastases through combined administration of anti-programmed cell death protein-1 (PD-1) antibody with evofosfamide and the IDO1 inhibitor epacadostat.Conclusions Improving therapeutic outcomes for patients with lung tumors, arising either as primary lesions or metastatic colonies, is of vital clinical importance. Building on preclinical evidence for IDO1's role in promoting inflammatory neovascularization of lung tumors, this study demonstrates how the intratumoral ischemic stress elicited by IDO1 inhibition can potentiate the immunogenic cytotoxicity of ischemia-targeted agents to effectively leverage immune checkpoint blockade responsiveness to confer a synergistic survival benefit. These findings provide a novel perspective on how IDO1 inhibitors can impact tumor biology and open up new possibilities for therapeutic applications.
Metrics
1 Record Views
Details
- Title
- Neovascular pruning by IDO1 inhibitors can potentiate immunogenic cytotoxicity of ischemia-targeted agents to synergistically enhance anti-PD-1 responsiveness
- Creators
- Shih-Chun Shen - Drexel UniversitySouvik Dey - WuXi AppTec (United States)James B. DuHadaway - Lankenau Institute for Medical ResearchErika Sutanto-Ward - Lankenau Institute for Medical ResearchMaurice T. Hampton - Ark Therapeutic (United States)Serguei Kozlov - NCI, Ctr Adv Preclin Res, Frederick Natl Lab Canc Res, Frederick, MD USAGeorge C. Prendergast - Thomas Jefferson UniversityAlexander J. Muller (Corresponding Author) - Lankenau Institute for Medical Research
- Publication Details
- Journal for immunotherapy of cancer, v 13(5), 011398
- Publisher
- Bmj Publishing Group
- Number of pages
- 17
- Grant note
- Lankenau Medical Center Foundation and Main Line Health 75N91019D00024 / National Cancer Institute, National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- College of Medicine
- Web of Science ID
- WOS:001500066700001
- Scopus ID
- 2-s2.0-105007033679
- Other Identifier
- 991022197431704721
UN Sustainable Development Goals (SDGs)
This publication has contributed to the advancement of the following goals:
Source: SDGs in the Output
InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Immunology
- Oncology