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Triggering interferon signaling in T cells with avadomide sensitizes CLL to anti-PD-L1/PD-1 immunotherapy.

用avadomide触发T细胞中的干扰素信号传导使CLL对anti-PD-L1/PD-1免疫疗法敏感。

  • 影响因子:7.27
  • DOI:10.1182/blood.2020006073
  • 作者列表:"Ioannou N","Hagner PR","Stokes M","Gandhi AK","Apollonio B","Fanous M","Papazoglou D","Sutton LA","Rosenquist R","Amini RM","Chiu H","Lopez-Girona A","Janardhanan P","Awan FT","Jones J","Kay NE","Shanafelt TD","Tallman MS","Stamatopoulos K","Patten PEM","Vardi A","Ramsay AG
  • 发表时间:2021-01-14
Abstract

:Cancer treatment has been transformed by checkpoint blockade therapies, with the highest anti-tumor activity of anti-programmed death 1 (PD-1) antibody therapy seen in Hodgkin lymphoma. Disappointingly, response rates have been low in the non-Hodgkin lymphomas, with no activity seen in relapsed/refractory chronic lymphocytic leukemia (CLL) with PD-1 blockade. Thus, identifying more powerful combination therapy is required for these patients. Here, we preclinically demonstrate enhanced anti-CLL activity following combinational therapy with anti-PD-1 or anti-PD-1 ligand (PD-L1) and avadomide, a cereblon E3 ligase modulator (CELMoD). Avadomide induced type I and II interferon (IFN) signaling in patient T cells, triggering a feedforward cascade of reinvigorated T-cell responses. Immune modeling assays demonstrated that avadomide stimulated T-cell activation, chemokine expression, motility and lytic synapses with CLL cells, as well as IFN-inducible feedback inhibition through upregulation of PD-L1. Patient-derived xenograft tumors treated with avadomide were converted to CD8+ T cell-inflamed tumor microenvironments that responded to anti-PD-L1/PD-1-based combination therapy. Notably, clinical analyses showed increased PD-L1 expression on T cells, as well as intratumoral expression of chemokine signaling genes in B-cell malignancy patients receiving avadomide-based therapy. These data illustrate the importance of overcoming a low inflammatory T-cell state to successfully sensitize CLL to checkpoint blockade-based combination therapy.

摘要

: 癌症治疗已经通过检查点阻断疗法转变,在霍奇金淋巴瘤中看到抗程序性死亡1 (PD-1) 抗体疗法的最高抗肿瘤活性。令人失望的是,在非霍奇金淋巴瘤中反应率低,而在PD-1阻断的复发性/难治性慢性淋巴细胞白血病 (CLL) 中未见活性。因此,需要对这些患者确定更有效的联合治疗。在这里,我们在临床前证明了在与anti-PD-1或anti-PD-1配体 (PD-L1) 和avadomide (一种cereblon E3连接酶调节剂 (CELMoD)) 联合治疗后,抗CLL活性增强。Avadomide在患者T细胞中诱导I型和II型干扰素 (IFN) 信号传导,触发恢复活力的T细胞应答的前馈级联。免疫建模试验表明,avadomide通过PD-L1的上调刺激了CLL细胞的T细胞活化、趋化因子表达、运动性和裂解突触,以及IFN诱导的反馈抑制。用avadomide治疗的患者来源的异种移植肿瘤转化为响应于anti-PD-L1/PD-1-based组合疗法的CD8 + T细胞发炎的肿瘤微环境。值得注意的是,临床分析显示,在接受基于avadomide的治疗的b细胞恶性肿瘤患者中,T细胞上的PD-L1表达以及趋化因子信号传导基因的瘤内表达增加。这些数据说明了克服低炎性T细胞状态以成功使CLL对基于检查点阻断的组合疗法敏感的重要性。

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影响因子:2.68
发表时间:2021-02-01
DOI:10.1080/14656566.2020.1814255
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发表时间:2021-03-24
DOI:10.1007/s11033-021-06299-9
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