Department of Green Bioengineering, Korea National University of Transportation, Chungju, 27469, Republic of Korea.
Department of Biomedical Science and BK21 PLUS Center for Creative Biomedical Scientists at Chonnam National University, Chonnam National University Medical School, Gwangju, 61469, Republic of Korea.
Adv Healthc Mater. 2021 Nov;10(21):e2100907. doi: 10.1002/adhm.202100907. Epub 2021 Sep 20.
Triple-negative breast cancer (TNBC) features immunologically "cold" tumor microenvironments with limited cytotoxic T lymphocyte (CTL) infiltration. Although ablation therapies have demonstrated modulation of "cold" TNBC tumors to inflamed "hot" tumors, recruitment of myeloid derived suppressor cells (MDSCs) at the tumors post ablation therapies prevents the infiltration of CTLs and challenge the antitumor potentials of T-cell therapies. Here, a thermal ablation immunotherapy strategy is developed to prevent the immune suppressive effects of MDSCs during photothermal ablation and induce a durable systemic antitumor immunity to eradicate TNBC tumors. An injectable pluronic F127/hyaluronic acid (HA)-based hydrogel embedded with manganese dioxide (BM) nanoparticles and TLR7 agonist resiquimod (R848) (BAGEL-R848), is synthesized to induce in situ laser-assisted gelation of the hydrogel and achieve desired ablation temperatures at a low laser-exposure time. Upon 808-nm laser irradiation, a significant reduction in the tumor burden is observed in BAGEL-R848-injected 4T1 tumor-bearing mice. The ablation induced immunogenic cell death and sustained release of R848 from BAGEL-R848 promotes dendritic cell maturation and reduced MDSCs localization in tumors. In addition, inflammatory M1 macrophages and CD8+IFN+ CTL are enriched in distant tumors in bilateral 4T1 tumor model, preventing metastatic tumor growth and signifying the potential of BAGEL-R848 to treat TNBC.
三阴性乳腺癌(TNBC)的肿瘤微环境具有免疫“冷”的特征,细胞毒性 T 淋巴细胞(CTL)浸润有限。虽然消融疗法已经证明可以将“冷”的 TNBC 肿瘤调节为炎症“热”肿瘤,但消融后肿瘤中髓系来源抑制细胞(MDSCs)的募集会阻止 CTL 的浸润,从而挑战 T 细胞疗法的抗肿瘤潜力。在这里,开发了一种热消融免疫治疗策略,以防止光热消融过程中 MDSCs 的免疫抑制作用,并诱导持久的全身抗肿瘤免疫,从而根除 TNBC 肿瘤。合成了一种可注射的基于聚(丙交酯-共-乙交酯)F127/透明质酸(HA)的水凝胶,其中嵌入了二氧化锰(BM)纳米颗粒和 TLR7 激动剂瑞喹莫德(R848)(BAGEL-R848),以诱导水凝胶的原位激光辅助凝胶化,并在低激光暴露时间内达到所需的消融温度。在 808nm 激光照射下,BAGEL-R848 注射的 4T1 荷瘤小鼠的肿瘤负担显著减轻。消融诱导的免疫原性细胞死亡和 BAGEL-R848 持续释放 R848 促进树突状细胞成熟,并减少肿瘤中 MDSCs 的定位。此外,在双侧 4T1 肿瘤模型中,炎性 M1 巨噬细胞和 CD8+IFN+CTL 在远处肿瘤中富集,阻止转移性肿瘤生长,表明 BAGEL-R848 具有治疗 TNBC 的潜力。
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