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Supplementary Figures S1-S5 from Microparticle-Delivered Cxcl9 Prolongs Braf Inhibitor Efficacy in Melanoma

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posted on 2023-05-03, 08:20 authored by Gabriele Romano, Francesca Paradiso, Peng Li, Pooja Shukla, Lindsay N. Barger, Olivia El Naggar, John P. Miller, Roger J. Liang, Timothy L. Helms, Alexander J. Lazar, Jennifer A. Wargo, Francesca Taraballi, James C. Costello, Lawrence N. Kwong

Supplementary Figures S1-S5

Funding

National Cancer Institute (NCI)

United States Department of Health and Human Services

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National Human Genome Research Institute (NHGRI)

United States Department of Health and Human Services

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Melanoma Research Foundation (MRF)

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ARTICLE 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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    Cancer Immunology Research

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