Neutralization of TGFβ Improves Tumor Immunity and Reduces Tumor Progression in Ovarian Carcinoma.
Neutralization of TGFβ Improves Tumor Immunity and Reduces Tumor Progression in Ovarian Carcinoma.
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DOI：
10.1158/1535-7163.mct-20-0412
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发表时间：
2021-03
影响因子：
5.7
通讯作者：
Arend RC
中科院分区：
文献类型：
--
作者：
Roane BM;Meza-Perez S;Katre AA;Goldsberry WN;Randall TD;Norian LA;Birrer MJ;Arend RC
转化生长因子-β(TGFR-β)的免疫抑制作用促进了肿瘤的发展，降低了对治疗的反应。在本研究中，我们使用Id8-P53−/−肿瘤作为高级别浆液性卵巢癌的小鼠模型。用抗三种转化生长因子-β配体的单抗中和转化生长因子-β。收集腹水和大网膜，用Flow检测T细胞反应的变化。注射肿瘤细胞后每隔一天接受抗转化生长因子-β治疗的小鼠，与未治疗的小鼠相比，腹水量减少(4.1vs0.7mLp<；0.001)，CD8/Treg比率提高(0.37vs2.5p=0.02)。在肿瘤攻击前进行单剂治疗，腹水体积(2.7mLvs.0.67mLp=0.002)和CD8/Tregs比率(0.36vs1.49；p=0.007)也有类似的减少，同时还显著减少了大网膜重量(114.9 vs93.4 mg；p=0.017)。在接种肿瘤细胞前开始治疗并持续6周，我们观察到类似的变化并延长了总生存期(中位数70天对57.5天)。转化生长因子-β中和导致肿瘤微环境内T细胞反应的有利变化，从而减缓卵巢癌的肿瘤进展。使用抗转化生长因子-β治疗可能是卵巢癌患者改善临床疗效的一种选择，值得进一步研究。
The immunosuppressive effects of transforming growth factor-beta (TGF-β) promotes tumor progression and diminishes response to therapy. In this study we used ID8-p53−/− tumors as a murine model of high grade serous ovarian cancer. A monoclonal antibody targeting all three TGF-β ligands was used to neutralize TGF-β. Ascites and omentum were collected and changes in T cell response were measured using flow. Treatment with anti-TGF-β therapy every other day following injection of tumor cells resulted in decreased ascites volume (4.1 vs 0.7mL; p < 0.001) and improved CD8:Treg ratio (0.37 vs 2.5; p = 0.02) compared to untreated mice. A single dose of therapy prior to tumor challenge, resulted in a similar reduction of ascites volume (2.7 vs. 0.67mL p = 0.002) and increased CD8:Tregs ratio (0.36 vs 1.49; p = 0.007), while also significantly reducing omental weight (114.9 vs 93.4mg; p = 0.017). Beginning treatment before inoculation with tumor cells and continuing for 6 weeks, we observe similar changes and prolonged overall survival (median 70 vs 57.5 days). TGF-β neutralization results in favorable changes to the T-cell response within the tumor microenvironment leading to decreased tumor progression in ovarian cancer. The utilization of anti-TGF-β therapy may be an option for management in ovarian cancer patients to improve clinical and warrants further investigation.