Microparticle-Delivered Cxcl9 Prolongs Braf Inhibitor Efficacy in Melanoma

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

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)558-569
Number of pages12
JournalCancer immunology research
Volume11
Issue number5
DOIs
StatePublished - May 1 2023

Keywords

  • Animals
  • Mice
  • Cell Line, Tumor
  • Melanoma/drug therapy
  • Mitogen-Activated Protein Kinase Kinases
  • Mutation
  • Neoplasm Recurrence, Local
  • Protein Kinase Inhibitors/pharmacology
  • Proto-Oncogene Proteins B-raf/genetics

ASJC Scopus subject areas

  • Medicine(all)

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