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Microparticle-delivered Cxcl9 delays the relapse of Braf inhibitor-treated melanoma

Gabriele Romano, Francesca Paradiso, John P Miller, Roger J Liang, Jennifer A Wargo, Francesca Taraballi, James C Costello, Lawrence N Kwong
doi: https://doi.org/10.1101/2022.05.24.493271
Gabriele Romano
1Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania
2Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas
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  • For correspondence: gr476@drexel.edu LKwong@mdanderson.org
Francesca Paradiso
3Center for Musculoskeletal Regeneration, Department of Orthopedics & Sports Medicine, Houston Methodist Research Institute, Houston, Texas
4Reproductive Biology and Gynaecological Oncology Group, Swansea University Medical School, Swansea, United Kingdom
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John P Miller
5Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas
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Roger J Liang
2Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas
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Jennifer A Wargo
6Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
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Francesca Taraballi
3Center for Musculoskeletal Regeneration, Department of Orthopedics & Sports Medicine, Houston Methodist Research Institute, Houston, Texas
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James C Costello
7Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
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Lawrence N Kwong
2Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas
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  • For correspondence: gr476@drexel.edu LKwong@mdanderson.org
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ABSTRACT

BRAF-mutant melanoma patients show significant responses to combined BRAF and MEK inhibition, but most patients relapse within 2 years. A major reservoir for such drug resistance is minimal residual disease (MRD), which is 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 timecourse analysis of tumors after BrafV600E extinction revealed that after an initial surge of immune activation, tumors later became immunologically “cold” after MRD establishment, suggesting an immune-suppressive/evasive phenotype. Computational analysis identified candidate T-cell recruiting chemokines that may be central players in the process, being strongly upregulated initially and then steeply decreasing as the immune response faded. As a result, we hypothesized that sustaining the chemokine signaling could impair MRD maintenance through increased recruitment of effector T-cells. We show that intratumoral administration of recombinant Cxcl9, either naked or loaded in microparticles, significantly impaired the relapse of MRD in BRAF-inhibited tumors. Our experiments constitute a proof of concept that chemokine-based microparticle delivery systems are a potential strategy to forestall tumor relapse and thus improve the clinical success of frontline treatment methods.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Financial Support: L.N.K. is supported by 1R01CA251608-01, 1R01HG011356-01, Melanoma Research Alliance 508743; J.C.C. is supported by U01CA231978; L.N.K. and F.T are supported by Melanoma Research Foundation 717906.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 25, 2022.
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Microparticle-delivered Cxcl9 delays the relapse of Braf inhibitor-treated melanoma
Gabriele Romano, Francesca Paradiso, John P Miller, Roger J Liang, Jennifer A Wargo, Francesca Taraballi, James C Costello, Lawrence N Kwong
bioRxiv 2022.05.24.493271; doi: https://doi.org/10.1101/2022.05.24.493271
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Microparticle-delivered Cxcl9 delays the relapse of Braf inhibitor-treated melanoma
Gabriele Romano, Francesca Paradiso, John P Miller, Roger J Liang, Jennifer A Wargo, Francesca Taraballi, James C Costello, Lawrence N Kwong
bioRxiv 2022.05.24.493271; doi: https://doi.org/10.1101/2022.05.24.493271

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