Blockade of the checkpoint inhibitor programmed death 1 (PD1) has demonstrated remarkable success in the clinic for the treatment of cancer; however, a majority of tumors are resistant to anti-PD1 monotherapy. Numerous ongoing clinical combination therapy studies will likely reveal additional therapeutics that complement anti-PD1 blockade. Recent studies found that immunogenic cell death (ICD) improves T cell responses against different tumors, thus indicating that ICD may further augment antitumor immunity elicited by anti-PD1. Here, we observed antitumor activity following combinatorial therapy with anti-PD1 Ab and the cyclin-dependent kinase inhibitor dinaciclib in immunocompetent mouse tumor models. Dinaciclib induced a type I IFN gene signature within the tumor, leading us to hypothesize that dinaciclib potentiates the effects of anti-PD1 by eliciting ICD. Indeed, tumor cells treated with dinaciclib showed the hallmarks of ICD including surface calreticulin expression and release of high mobility group box 1 (HMGB1) and ATP. Mice treated with both anti-PD1 and dinaciclib showed increased T cell infiltration and DC activation within the tumor, indicating that this combination improves the overall quality of the immune response generated. These findings identify a potential mechanism for the observed benefit of combining dinaciclib and anti-PD1, in which dinaciclib induces ICD, thereby converting the tumor cell into an endogenous vaccine and boosting the effects of anti-PD1.

中文翻译：

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Dinaciclib诱导免疫原性细胞死亡并增强抗PD1介导的肿瘤抑制

在临床上，对检查点抑制剂程序性死亡1（PD1）的阻断已显示出显着的成功。但是，大多数肿瘤对抗PD1单药治疗有抗药性。正在进行的大量临床组合疗法研究可能会揭示出补充抗PD1阻断作用的其他疗法。最近的研究发现，免疫原性细胞死亡（ICD）可以改善针对不同肿瘤的T细胞反应，从而表明ICD可以进一步增强抗PD1引发的抗肿瘤免疫力。在这里，我们观察到了抗PD1 Ab和细胞周期蛋白依赖性激酶抑制剂dinaciclib联合治疗后，在具有免疫功能的小鼠肿瘤模型中的抗肿瘤活性。Dinaciclib诱导了肿瘤内的I型IFN基因签名，导致我们假设dinaciclib通过引发ICD来增强抗PD1的作用。确实，用dinaciclib处理的肿瘤细胞显示出ICD的特征，包括表面钙网蛋白表达和高迁移率族1号盒（HMGB1）和ATP的释放。用抗PD1和dinaciclib治疗的小鼠在肿瘤内显示出增加的T细胞浸润和DC活化，表明这种组合可改善所产生免疫反应的整体质量。这些发现确定了将dinaciclib和抗PD1结合起来观察到的益处的潜在机制，其中dinaciclib诱导ICD，从而将肿瘤细胞转化为内源性疫苗并增强了抗PD1的作用。用dinaciclib处理的肿瘤细胞具有ICD的标志，包括表面钙网蛋白表达和高迁移率族1号框（HMGB1）和ATP的释放。用抗PD1和dinaciclib治疗的小鼠在肿瘤内显示出增加的T细胞浸润和DC活化，表明这种组合可改善所产生免疫反应的整体质量。这些发现确定了将dinaciclib和抗PD1结合起来观察到的益处的潜在机制，其中dinaciclib诱导ICD，从而将肿瘤细胞转化为内源性疫苗并增强了抗PD1的作用。用dinaciclib处理的肿瘤细胞具有ICD的标志，包括表面钙网蛋白表达和高迁移率族1号框（HMGB1）和ATP的释放。用抗PD1和dinaciclib治疗的小鼠在肿瘤内显示出增加的T细胞浸润和DC活化，表明这种组合可改善所产生免疫反应的整体质量。这些发现确定了将dinaciclib和抗PD1结合起来观察到的益处的潜在机制，其中dinaciclib诱导ICD，从而将肿瘤细胞转化为内源性疫苗并增强了抗PD1的作用。表明该组合改善了所产生免疫反应的整体质量。这些发现确定了将dinaciclib和抗PD1结合起来观察到的益处的潜在机制，其中dinaciclib诱导ICD，从而将肿瘤细胞转化为内源性疫苗并增强了抗PD1的作用。表明该组合改善了所产生免疫反应的整体质量。这些发现确定了将dinaciclib和抗PD1结合起来观察到的益处的潜在机制，其中dinaciclib诱导ICD，从而将肿瘤细胞转化为内源性疫苗并增强了抗PD1的作用。