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

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 Braf^V600E-driven melanoma MRD wherein genetic Braf^V600E extinction leads to strong but incomplete tumor regression. Transcriptional timecourse analysis of tumors after Braf^V600E 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.