RT Journal Article
SR Electronic
T1 Microparticle-delivered Cxcl9 delays the relapse of Braf inhibitor-treated melanoma
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.05.24.493271
DO 10.1101/2022.05.24.493271
A1 Gabriele Romano
A1 Francesca Paradiso
A1 John P Miller
A1 Roger J Liang
A1 Jennifer A Wargo
A1 Francesca Taraballi
A1 James C Costello
A1 Lawrence N Kwong
YR 2022
UL http://biorxiv.org/content/early/2022/05/25/2022.05.24.493271.abstract
AB 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 StatementThe authors have declared no competing interest.