Abigael Chaouat, Yona Kalechman, Ophir Hay, Julia E Manoim, Tal Lantner, Eitan Niderberg, Hagit Hauschner, Dvora Kenigsbuch Sredni, Tal Cohen, Agata Schlesinger, Ronia Nadler, Mira Barda-Saad, Elad Noy, Michael Albeck, Dan L Longo, Benjamin Sredni
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引用次数: 0
摘要
抑制程序性死亡-1/程序性死亡配体 1(PD-1/PD-L1)轴活性的各种癌症治疗方法已经开发出来,PD-1/PD-L1 轴是肿瘤免疫逃避的关键角色。我们的研究表明,免疫调节小碲复合物 AS101(三氯(二氧代乙烯-o,o')碲酸铵)和 SAS(八-O-双(R,R)-酒石酸二碲酸铵)通过调节 α4β1 很晚抗原-4(VLA-4)整合素的活性,抑制了 PD-L1 在多种人类和小鼠恶性细胞中的表达。因此,pAkt 及其下游效应物 pNFκB 的表达受到抑制。此外,SAS 还能促进活化的合成脾细胞或 CD8+ T 细胞杀死小鼠恶性细胞,防止恶性细胞产生化疗抵抗。此外,AS101 和 SAS 还可通过抑制 VLA-4/IL-10/PD-L1 通路至少部分提高化疗敏感性。此外,AS101或SAS治疗B16/F10黑色素瘤小鼠可降低肿瘤细胞PD-L1的表达,从而增加CD8+ T细胞对肿瘤的浸润并缩小肿瘤。αPD-1抗体和任一种碲化合物的联合治疗可显著提高免疫疗法的抗肿瘤疗效。总之,VLA-4整合素信号对肿瘤免疫逃避至关重要,是癌症治疗的潜在靶点。最后,具有生物活性的碲化合物 AS101 或 SAS 可以有效提高基于 αPD-1 的癌症免疫疗法的疗效。
Inhibition of α4β1 Integrin Activity by Small Tellurium Compounds Regulates PD-L1 Expression and Enhances Antitumor Effects.
Various cancer treatment approaches that inhibit the activity of the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) axis, a key player in tumor immune evasion, have been developed. We show that the immunomodulatory small tellurium complexes AS101 (ammonium trichloro(dioxoethylene-o,o')tellurate) and SAS (octa-O-bis(R,R)-tartarate ditellurane) suppress PD-L1 expression in a variety of human and mouse malignant cells via the modulation of α4β1 very late antigen-4 (VLA-4) integrin activity. Consequently, the expression of pAkt and its downstream effector pNFκB are inhibited. Additionally, SAS promotes the death of mouse malignant cells by activated syngeneic splenocytes or CD8+ T cells, preventing the development of chemoresistance in malignant cells. Moreover, AS101 and SAS may increase, at least in part, chemosensitivity through inhibition of the VLA-4/IL-10/PD-L1 pathway. Additionally, AS101 or SAS treatment of B16/F10 melanoma-bearing mice decreased tumor cell PD-L1 expression, leading to increased CD8+ T-cell infiltration into the tumors and tumor shrinkage. Combination treatment with an αPD-1 antibody and either tellurium compound significantly increased the antitumor efficacy of immunotherapy. Overall, VLA-4 integrin signaling is critical for tumor immune evasion and is a potential target for cancer treatment. Finally, AS101 or SAS, biologically active tellurium compounds, can effectively enhance the therapeutic efficacy of αPD-1-based cancer immunotherapy.
期刊介绍:
The International Journal of Biological Sciences is a peer-reviewed, open-access scientific journal published by Ivyspring International Publisher. It dedicates itself to publishing original articles, reviews, and short research communications across all domains of biological sciences.