PI3Kgamma Inhibitor Attenuates Immunosuppressive Effect of Poly(l-Glutamic Acid)-Combretastatin A4 Conjugate in Metastatic Breast Cancer
PI3Kgamma Inhibitor Attenuates Immunosuppressive Effect of Poly(l-Glutamic Acid)-Combretastatin A4 Conjugate in Metastatic Breast Cancer
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PI3Kgamma 抑制剂减弱聚（L-谷氨酸）-Combretastatin A4 缀合物对转移性乳腺癌的免疫抑制作用
DOI：
10.1002/advs.201900327
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发表时间：
2019-06-19
期刊：
影响因子：
15.1
通讯作者：
Chen, Xuesi
中科院分区：
文献类型：
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作者：
Qin, Hanjiao;Yu, Haiyang;Chen, Xuesi
血管阻断剂（VDA）在癌症治疗中具有巨大的潜力。聚（L-谷氨酸）-考布他汀A4缀合物（PLG-CA 4）是一类新型VDA。虽然它具有显著的抗肿瘤活性，但它可以诱导促进肿瘤生长的宿主免疫应答。在此，PLG-CA 4诱导4 T1转移性乳腺癌中肿瘤相关巨噬细胞（TAM）向M2样表型极化（对照30% vs PLG-CA 4 53%; p < 0.05）。与PLG-CA 4单药治疗相比，磷酸肌醇3-激酶γ（PI 3 K γ）的抑制通过减少M2样TAM的数量（每个肿瘤2.0 x 10（4）至1.5 x 10（4））和细胞毒性T淋巴细胞的潜在增强（每个肿瘤3.0 x 10（4）至5.7 x 10（4））减弱PLG-CA 4治疗的免疫抑制作用。重要的是，PI 3 K γ抑制剂与PLG-CA 4协同作用显著延长了平均存活时间，从单药治疗小鼠的52天延长至61.8天。此外，PLG-CA 4和PI 3 K γ抑制剂的组合改善了NLG 919（免疫检查点吲哚胺2，3-双加氧酶（IDO）的抑制剂）的肿瘤治疗效果。就目前所知，这是第一个证明VDA诱导巨噬细胞重塑为M2样表型的研究。研究结果还表明，VDA与肿瘤中精确的免疫调节剂组合的潜在治疗策略可以逆转免疫耐药性。
Vascular disrupting agents (VDAs) have great potential for cancer treatment. Poly(l-glutamic acid)-combretastatin A4 conjugate (PLG-CA4) is a novel class of VDAs. Though it has notable antitumor activity, it can induce host immune responses that promote tumor growth. Here, PLG-CA4 induces the polarization of tumor-associated macrophages (TAMs) toward the M2-like phenotype in 4T1 metastatic breast cancer (Control 30% vs PLG-CA4 53%; p < 0.05). Compared to the monotherapy of PLG-CA4, inhibition of phosphoinositide 3-kinase gamma (PI3K gamma) attenuates the immunosuppressive effect of PLG-CA4 treatment by decreasing the number of M2-like TAMs (2.0 x 10(4) to 1.5 x 10(4) per tumor) and potential enhancement of cytotoxic T lymphocyte (3.0 x 10(4) to 5.7 x 10(4) per tumor). Importantly, PI3K gamma inhibitor synergizing with PLG-CA4 significantly extends the mean survival time from 52 days in monotherapy-treated mice to 61.8 days. Additionally, the combination of PLG-CA4 and PI3K gamma inhibitor improves the tumor therapeutic effect of NLG919, an inhibitor of immune checkpoint indoleamine 2,3-dioxygenase (IDO). As far as it is known, this is the first demonstrated study that VDAs induce the reshaping of macrophages to the M2-like phenotype. The findings also indicate a potential therapeutic strategy of the combination VDAs with an accurate immune modifier in the tumor to reverse the immune resistance.