Bromodomain and extra-terminal (BET) proteins are attractive targets for treating various malignancies including melanoma. The inhibition of BET bromodomains, e.g. with JQ1, is found to downregulate the expression of both c-MYC oncoprotein and programmed cell death ligand 1 (PD-L1), which play a crucial role in tumor growth and the immunosuppressive tumor microenvironment, respectively. The BET bromodomain inhibitors like JQ1 though exhibiting high selectivity and affinity show usually low bioavailability and efficacy in vivo due to fast clearance and inferior uptake by tumor cells. The therapeutic effect of JQ1 might further be lowered by drug resistance. Here, enzyme-responsive micellar JQ1 (mJQ1) was fabricated from a poly(ethylene glycol)-b-poly(L-tyrosine) copolypeptide to enhance JQ1 delivery and the immunotherapy of malignant melanoma. The in vitro results showed that mJQ1 induced clearly better repression of c-MYC and PD-L1 proteins, cell cycle arrest, cell inhibition, and apoptotic activity than free JQ1 in B16F10 cancer cells. The intratumoral administration of mJQ1 at 2.5 mg of JQ1 equiv. per kg was found to show better inhibition of B16F10 tumors in C57BL/6 mice than the intraperitoneal administration of free JQ1 at 50 mg kg⁻¹. In particular, when combined with radiotherapy, mJQ1 effectively suppressed tumor growth and brought about strong local and systemic antitumor immunity as evidenced by elevated CD8+ T cells and increased ratios of CD8+ T cells to Tregs, affording significantly improved survival of B16F10 tumor-bearing mice than their JQ1 counterparts and marked growth suppression of distant tumors. The great potency of enzyme-responsive micellar JQ1 makes it interesting for immunotherapy of various tumors.

中文翻译：

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酶反应胶束 JQ1 诱导增强的 BET 蛋白抑制和恶性肿瘤的免疫治疗

溴结构域和末端外 (BET) 蛋白是治疗各种恶性肿瘤（包括黑色素瘤）的有吸引力的靶标。发现BET 溴结构域的抑制（例如JQ1）会下调 c-MYC 癌蛋白和程序性细胞死亡配体 1 (PD-L1) 的表达，它们分别在肿瘤生长和免疫抑制性肿瘤微环境中起关键作用。像 JQ1 这样的 BET 溴结构域抑制剂虽然表现出高选择性和亲和力，但由于快速清除和肿瘤细胞吸收较差，通常在体内显示出低生物利用度和功效。JQ1的治疗效果可能会因耐药性而进一步降低。在这里，酶响应胶束 JQ1 (mJQ1) 是由聚（乙二醇）-b - poly （L-酪氨酸）共聚肽增强 JQ1 递送和恶性黑色素瘤的免疫治疗。的体外结果表明，mJQ1诱导的c-MYC和PD-L1蛋白，细胞周期停滞，细胞抑制，而且比在B16F10肿瘤细胞游离JQ1凋亡活性的明显更好的抑制。mJQ1 的肿瘤内给药剂量为 2.5 mg JQ1 当量。发现每千克对 C57BL/6 小鼠 B16F10 肿瘤的抑制作用比腹膜内给予 50 mg kg ^-1的游离 JQ1 更好. 特别是，当与放疗相结合时，mJQ1 有效抑制肿瘤生长并带来强大的局部和全身抗肿瘤免疫，如 CD8+ T 细胞升高和 CD8+ T 细胞与 Tregs 比率增加，显着提高了 B16F10 荷瘤小鼠的存活率。他们的 JQ1 对应物和远处肿瘤的显着生长抑制。酶反应胶束 JQ1 的强大效力使其在各种肿瘤的免疫治疗中变得有趣。