Microparticle-Delivered Cxcl9 Prolongs Braf Inhibitor Efficacy in Melanoma.
Microparticle-Delivered Cxcl9 Prolongs Braf Inhibitor Efficacy in Melanoma.
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DOI：
10.1158/2326-6066.cir-22-0224
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发表时间：
2023-05-03
影响因子：
10.1
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中科院分区：
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BRAF突变黑色素瘤患者对BRAF和MEK联合抑制表现出显着反应，但大多数在2年内复发。耐药性的一个主要储存库是微小残留病（MRD），由处于休眠状态的耐药肿瘤细胞组成。为了利用MRD的潜在治疗弱点，我们建立了BrafV600E驱动的黑色素瘤MRD的基因工程小鼠模型，其中基因BrafV600E消退导致强烈但不完全的肿瘤消退。BrafV600E消失后的转录时程分析显示，在最初的免疫激活激增后，肿瘤在MRD建立后变得免疫学上“冷”。计算分析确定候选T细胞募集趋化因子最初强烈上调，并随着免疫应答消退而急剧下降。因此，我们假设持续的趋化因子信号可能通过增加效应T细胞的募集来损害MRD的维持。我们发现，裸的或装载在微粒中的重组Cxcl9（rCxcl9）的肿瘤内施用显著损害BRAF抑制的肿瘤中的MRD复发，包括微粒递送的rCxcl9与BRAF和MEK抑制组合后的几种完全病理学应答。我们的实验证明了基于趋化因子的微粒递送系统是预防肿瘤复发的潜在策略，从而提高了一线治疗方法的临床成功率。作者表明，微粒介导的Cxcl9递送将效应T细胞募集到肿瘤部位并延迟复发。这些数据表明，与靶向治疗或免疫治疗相结合的辅助方法可以增强免疫应答。
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 frontline treatment methods. The authors show that microparticle-mediated delivery of Cxcl9 recruits effector T cells to the tumor site and delays relapse. The data suggest an adjuvant approach to boost the immune response in combination with targeted therapy or immunotherapy.