Combination Therapy of Mithramycin A and Immune Checkpoint Inhibitor for the Treatment of Colorectal Cancer in an Orthotopic Murine Model.
Combination Therapy of Mithramycin A and Immune Checkpoint Inhibitor for the Treatment of Colorectal Cancer in an Orthotopic Murine Model.
复制标题
DOI：
10.3389/fimmu.2021.706133
复制
发表时间：
2021
影响因子：
7.3
通讯作者：
Mohapatra S
中科院分区：
文献类型：
--
作者：
Dutta R;Khalil R;Mayilsamy K;Green R;Howell M;Bharadwaj S;Mohapatra SS;Mohapatra S
程序性细胞死亡-1受体（PD-1）轴及其配体（PD-L1）在结直肠癌（CRC）逃避免疫监视中起关键作用，并且已发现阻断该轴对一部分患者有效。尽管阻断PD-L1已被证明对5-10%的患者有效，但大多数队列显示对这种检查点阻断（CB）治疗有耐药性。多种因素参与了CB耐药的生长，其中T细胞衰竭和肿瘤微环境（tumor microenvironment， TME）中免疫细胞的免疫抑制作用与其他肿瘤内在因素一起起着至关重要的作用。我们之前已经在皮下小鼠模型中证明了聚酮类抗生素米特霉素- a （Mit-A）是体外和体内杀死癌症干细胞（CSCs）的有效药物。由于TME在CB治疗中起着关键作用，我们在免疫活性MC38同基因原位CRC小鼠模型中测试了Mit-A与抗pd - l1单抗（αPD-L1）联合治疗的免疫调节效果。通过流式细胞术分析肿瘤和脾脏中受治疗影响的不同免疫细胞群，以及肿瘤样本的RT-PCR。我们证明了联合治疗可以减少肿瘤生长，从而提高了CB的有效性。αPD-L1存在时，Mit-A显著增加TME中CD8+ T细胞浸润，降低免疫抑制性粒细胞髓源性抑制细胞和抗炎巨噬细胞。我们的研究结果表明，Mit-A联合αPD-L1具有通过将CRC中的免疫“冷”TME转化为“热”TME而增强CB治疗的潜力。
The axis of Programmed cell death-1 receptor (PD-1) with its ligand (PD-L1) plays a critical role in colorectal cancer (CRC) in escaping immune surveillance, and blocking this axis has been found to be effective in a subset of patients. Although blocking PD-L1 has been shown to be effective in 5–10% of patients, the majority of the cohorts show resistance to this checkpoint blockade (CB) therapy. Multiple factors assist in the growth of resistance to CB, among which T cell exhaustion and immunosuppressive effects of immune cells in the tumor microenvironment (TME) play a critical role along with other tumor intrinsic factors. We have previously shown the polyketide antibiotic, Mithramycin-A (Mit-A), an effective agent in killing cancer stem cells (CSCs) in vitro and in vivo in a subcutaneous murine model. Since TME plays a pivotal role in CB therapy, we tested the immunomodulatory efficacy of Mit-A with anti-PD-L1 mAb (αPD-L1) combination therapy in an immunocompetent MC38 syngeneic orthotopic CRC mouse model. Tumors and spleens were analyzed by flow cytometry for the distinct immune cell populations affected by the treatment, in addition to RT-PCR for tumor samples. We demonstrated the combination treatment decreases tumor growth, thus increasing the effectiveness of the CB. Mit-A in the presence of αPD-L1 significantly increased CD8+ T cell infiltration and decreased immunosuppressive granulocytic myeloid-derived suppressor cells and anti-inflammatory macrophages in the TME. Our results revealed Mit-A in combination with αPD-L1 has the potential for augmented CB therapy by turning an immunologically “cold” into “hot” TME in CRC.
登录
查看更多内容
影响因子：
7.2
作者：
Lu, Chunwan;Redd, Priscilla S.;Liu, Kebin
通讯作者：
Liu, Kebin
DOI：
10.1084/jem.20160801
发表时间：
2017-04-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Juneja VR;McGuire KA;Manguso RT;LaFleur MW;Collins N;Haining WN;Freeman GJ;Sharpe AH
通讯作者：
Sharpe AH
影响因子：
--
作者：
Li, Jiasu;Gao, Hongmei;Yin, Lin
通讯作者：
Yin, Lin
抗癌药毛霉素A A将肿瘤细胞对肿瘤坏死因子（TNF）诱导的凋亡敏感。
影响因子：
8.8
作者：
Duverger, V;Murphy, AM;Sheehan, D;England, K;Cotter, TG;Hayes, I;Murphy, FJ
通讯作者：
Murphy, FJ
影响因子：
28.2
作者：
Llosa, Nicolas J.;Cruise, Michael;Housseau, Franck
通讯作者：
Housseau, Franck