Carfilzomib modulates tumor microenvironment to potentiate immune checkpoint therapy for cancer.
Carfilzomib modulates tumor microenvironment to potentiate immune checkpoint therapy for cancer.
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卡非佐米调节肿瘤微环境以增强癌症免疫检查点治疗
DOI：
10.15252/emmm.202114502
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发表时间：
2022-01-11
影响因子：
11.1
通讯作者：
Chen L
中科院分区：
文献类型：
--
作者：
Zhou Q;Liang J;Yang T;Liu J;Li B;Li Y;Fan Z;Wang W;Chen W;Yuan S;Xu M;Xu Q;Luan Z;Xia Z;Zhou P;Huang Y;Chen L
PD-1抑制剂在部分癌症患者上的临床疗效令人印象深刻。然而，仍然迫切需要开发有效的增效剂来扩大其临床应用。肿瘤相关巨噬细胞()是一种M2极化的巨噬细胞，它能消除或抑制T细胞介导的抗肿瘤反应。将TAMs转化为M1巨噬细胞是一种诱人的抗肿瘤治疗策略。在这里，我们进行了高通量筛选，发现卡菲佐米能有效地驱动M2巨噬细胞表达M1细胞因子，吞噬肿瘤细胞，并将抗原呈递给T细胞。机制上，卡菲佐米诱导M2巨噬细胞未折叠蛋白反应，激活IRE1α募集TRAF2，激活NF-κB转录编码M1标记基因。在体内，Carfilzomib通过将TAMs重新编程为类M1巨噬细胞，有效地重塑了肿瘤微环境，并在转基因小鼠模型中缩小了原位肺癌。更重要的是，卡菲佐米与PD-1抗体有协同作用，几乎完全消退了原发肺癌。鉴于Carfilzomib在临床上的安全性，我们的工作建议立即应用Carfilzomib和PD-1抑制剂联合治疗实体瘤患者。肿瘤相关巨噬细胞(TAM)具有高度的免疫抑制作用。进行了高通量药物筛选，以确定FDA批准的可以将TAMs重新编程为免疫刺激M1巨噬细胞的药物。
Impressive clinical benefit is seen in clinic with PD‐1 inhibitors on portion of cancer patients. Yet, there remains an urgent need to develop effective synergizers to expand their clinical application. Tumor‐associated macrophage (TAM), a type of M2‐polarized macrophage, eliminates or suppresses T‐cell‐mediated anti‐tumor responses. Transforming TAMs into M1 macrophages is an attractive strategy of anti‐tumor therapy. Here, we conducted a high‐throughput screening and found that Carfilzomib potently drove M2 macrophages to express M1 cytokines, phagocytose tumor cells, and present antigens to T cells. Mechanistically, Carfilzomib elicited unfolded protein response (UPR), activated IRE1α to recruit TRAF2, and activated NF‐κB to transcribe genes encoding M1 markers in M2 macrophages. In vivo, Carfilzomib effectively rewired tumor microenvironment through reprogramming TAMs into M1‐like macrophages and shrank autochthonous lung cancers in transgenic mouse model. More importantly, Carfilzomib synergized with PD‐1 antibody to almost completely regress autochthonous lung cancers. Given the safety profiles of Carfilzomib in clinic, our work suggested a potentially immediate application of combinational treatment with Carfilzomib and PD‐1 inhibitors for patients with solid tumors. Tumor‐associated macrophages (TAMs) are highly immunosuppressive. A high‐throughput drug screening was performed to identify FDA‐approved drugs that can reprogram TAMs into immunostimulatory M1 macrophages.