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Accepted (AM)Open Access (License Unspecified), Open
Journal article
Microparticle-Delivered Cxcl9 Prolongs Braf Inhibitor Efficacy in Melanoma
Cancer immunology research, v 11(5), pp 558-569
03 May 2023
PMID: 36820825
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Patients with BRAF-mutant melanoma show substantial responses to combined BRAF and MEK inhibition, but most relapse within 2 years. A major reservoir for drug resistance is minimal residual disease (MRD), comprised of drug-tolerant tumor cells laying in a dormant state. Towards exploiting potential therapeutic vulnerabilities of MRD, we established a genetically engineered mouse model of BrafV600E-driven melanoma MRD wherein genetic BrafV600E extinction leads to strong but incomplete tumor regression. Transcriptional time-course analysis after BrafV600E extinction revealed that after an initial surge of immune activation, tumors later became immunologically "cold" after MRD establishment. Computational analysis identified candidate T-cell recruiting chemokines as strongly upregulated initially and steeply decreasing as the immune response faded. Therefore, we hypothesized that sustaining chemokine signaling could impair MRD maintenance through increased recruitment of effector T cells. We found that intratumoral administration of recombinant Cxcl9 (rCxcl9), either naked or loaded in microparticles, significantly impaired MRD relapse in BRAF-inhibited tumors, including several complete pathologic responses after microparticle-delivered rCxcl9 combined with BRAF and MEK inhibition. Our experiments constitute proof of concept that chemokine-based microparticle delivery systems are a potential strategy to forestall tumor relapse and thus improve the clinical success of first-line treatment methods.
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Details
- Title
- Microparticle-Delivered Cxcl9 Prolongs Braf Inhibitor Efficacy in Melanoma
- Creators
- Gabriele Romano - Drexel University, Pharmacology and PhysiologyFrancesca Paradiso - Houston MethodistPeng Li - Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TexasPooja Shukla - The University of Texas MD Anderson Cancer CenterLindsay N Barger - Drexel UniversityOlivia El Naggar - Drexel UniversityJohn P Miller - The University of Texas MD Anderson Cancer CenterRoger J Liang - The University of Texas MD Anderson Cancer CenterTimothy L Helms - The University of Texas MD Anderson Cancer CenterAlexander J Lazar - The University of Texas MD Anderson Cancer CenterJennifer A Wargo - The University of Texas MD Anderson Cancer CenterFrancesca Taraballi - Methodist HospitalJames C Costello - Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, ColoradoLawrence N Kwong - The University of Texas MD Anderson Cancer Center
- Publication Details
- Cancer immunology research, v 11(5), pp 558-569
- Publisher
- American Association for Cancer Research (AACR)
- Grant note
- R01 CA251608 / NCI NIH HHS U01 CA231978 / NCI NIH HHS R01 HG011356 / NHGRI NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology; Pharmacology and Physiology
- Web of Science ID
- WOS:000986409100001
- Scopus ID
- 2-s2.0-85159541693
- Other Identifier
- 991021860726804721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Immunology
- Oncology