PO.TB10.16 · 肿瘤生物学
一种针对TNBC的新型双靶点策略:联合EZH2抑制与多巴胺D1受体激活以恢复免疫平衡
A novel dual-target strategy against TNBC: Combining EZH2 inhibition and dopamine D1 receptor activation to restore immune balance
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摘要 Abstract
中文摘要
三阴性乳腺癌(TNBC)仍是最具侵袭性且治疗上最具挑战性的乳腺癌亚型之一,其特征为高度异质性、内在耐药性和不良的免疫浸润。目前迫切需要毒性更低、既能抑制肿瘤生长又能重塑肿瘤微环境(TME)的方法。EZH2是一种组蛋白甲基转移酶,在TNBC中常过表达,与免疫抑制和疾病进展相关。我们此前报道,将GSK126(一种EZH2抑制剂)与A77636(一种多巴胺D1受体[DRD1]激动剂)联合使用,产生了优于单药治疗的抗肿瘤效果。我们假设协同靶向EZH2和DRD1可将免疫学上的"冷"TNBC微环境转变为"热"的、免疫容许状态,从而增强治疗疗效并克服耐药机制。将雌性NSG小鼠(4-6周龄)原位植入MDA-MB-231细胞,随机分为四个治疗组(n=8):赋形剂、GSK126(2 mg/kg)、A77636(50 mg/kg)或联合用药。治疗以腹腔注射方式每周给药一次,持续四周。每周及终点时测量肿瘤体积。通过流式细胞术分析肿瘤和免疫组织。与赋形剂和单药相比,联合治疗显著降低了肿瘤重量(平均差=0.278g,95% CI:0.109-0.446,p=0.0018)和体积(平均差=101 mm³,95% CI:51.7-151,p<0.0001)。值得注意的是,联合用药显著减少了血液和肿瘤组织中的单核细胞群,并下调了肿瘤相关单核细胞和中性粒细胞中的EZH2表达。动力学分析揭示了单核细胞的双相反应——初始Ly6C^hi募集,随后向Ly6C^lo转变。联合用药抑制了Ly6C^hi浸润(0.32对0.92;下降65%,p=0.0138),同时促进了Ly6C^lo积累(2.5对1.5;增加1.67倍,p=0.5126)。通过采用联合治疗策略重定向单核细胞表型,我们得以抑制促炎的IL-1beta环境,同时增强抗炎的IL-10信号——最终营造出一种抑制肿瘤的免疫环境。总之,对EZH2和DRD1的双重调节通过重塑免疫格局有效遏制了TNBC进展。这些发现揭示了一条独特的治疗途径,将表观遗传调控与多巴胺能激活相结合,以恢复TNBC中的免疫应答能力。(本工作由授予Eswar Shankar的DOD W81XWH2010065资助支持。)
查看英文原文 English abstract
Triple-negative breast cancer (TNBC) remains one of the most aggressive and therapeutically challenging breast cancer subtypes, characterized by high heterogeneity, intrinsic resistance, and poor immune infiltration. There is a critical unmet need for less toxic approaches that can both suppress tumor growth and remodel the tumor microenvironment (TME). EZH2, a histone methyltransferase, is frequently overexpressed in TNBC, associated with immunosuppression, and disease progression. We previously reported combining GSK126 (an EZH2 inhibitor) with A77636 (a dopamine D1 receptor [DRD1] agonist) produced superior antitumor effects compared to monotherapies. We hypothesized synergistic targeting of EZH2 and DRD1 would convert the immunologically “cold” TNBC microenvironment into a “hot,” immune-permissive state, thereby enhancing therapeutic efficacy and overcoming resistance mechanisms. Female NSG mice (4-6 weeks old) were orthotopically implanted with MDA-MB-231 cells, randomized into four treatment groups (n=8): vehicle, GSK126 (2 mg/kg), A77636 (50 mg/kg), or combination. Treatments were administered intraperitoneally weekly for four weeks. Tumor volume was measured weekly and at endpoint. Tumors and immune tissues were analyzed by flow cytometry. Combination therapy significantly reduced tumor weight (mean difference = 0.278g, 95% CI: 0.109-0.446, p =0.0018) and volume (mean difference = 101 mm³, 95% CI: 51.7-151, p <0.0001) compared with vehicle and single agents. Notably, the combination markedly decreased monocyte populations in both blood and tumor tissue and downregulated EZH2 expression in tumor-associated monocytes and neutrophils. Kinetic profiling revealed a biphasic monocyte response-initial Ly6C^hi recruitment followed by Ly6C^lo transition. The combination suppressed Ly6C^hi infiltration (0.32 vs. 0.92; 65% decrease, p =0.0138) while promoting Ly6C^lo accumulation (2.5 vs. 1.5; 1.67-fold increase, p =0.5126). By using a combinational treatment strategy to redirect monocyte phenotypes, we were able to suppress the pro-inflammatory IL-1beta environment while simultaneously enhancing anti-inflammatory IL-10 signaling-ultimately creating a tumor-suppressive immune milieu. In summary, dual modulation of EZH2 and DRD1 effectively halts TNBC progression by reshaping the immunological landscape. These findings uncover a distinctive therapeutic avenue that integrates epigenetic regulation with dopaminergic activation to restore immune responsiveness in TNBC. (This work was supported by DOD W81XWH2010065 to Eswar Shankar).
利益披露 Disclosure
R. Shukla, None..
K. Ormiston, None..
G. Sarathy, None..
S. Dhekne, None..
D. M. Quiroga, None..
S. Gupta, None..
P. Giglio, None..
C. Rolfo, None..
E. Shankar, None.