Characterization of an inflammasome-unleashing approach to improve anti-PD-1 therapy in cancer

摘要 阻断免疫检查点PD-1/PD-L1增加了各种不同疾病的总体和无进展存活率 癌症。然而，只有数量有限的患者显示出临床益处。了解相关机制 通过抗PD-1抗体调节疲惫的CD8 T细胞来改进这一方法是强制性的。在这 背景，炎症在T细胞耗竭和肿瘤免疫治疗中所起的作用存在争议。 对各种小鼠模型和人类黑色素瘤队列的观察支持这样一种观点，即激活 先天免疫因素，如炎症性小体，可能在抗PD-1治疗中发挥关键作用。然而，我们需要 确定分子靶点以触发炎症小体激活，可能导致改进的抗PD-1治疗。 TMEM176B是一种由2型树突状细胞(CDC2)强烈表达的细胞内阳离子通道 这通过离子机制抑制了炎症体的激活。波利替尼，一种有效的TMEM176B抑制剂， 在Tem176b中诱导肿瘤生长控制并增强抗PD-1抗体的抗肿瘤活性， 淋巴瘤、黑色素瘤、肺癌和结肠癌中炎症体和CD8T细胞依赖方式的研究 模特们。然而，CD8 T细胞增强的机制仍不清楚。这个项目的目标是 确定Boritinib改善抗PD-1治疗的机制，为临床奠定基础 对化合物的评价。我们已发表和未发表的结果促使我们提出炎症体 由Boritinib疗法触发的激活可能通过一种机制调节耗尽的CD8 T细胞亚群 涉及Th17细胞。我们将开展一项涉及体内功能研究和生物信息学的研究计划 基于三个具体目标的分析。在具体目标1中，我们希望确认和补充我们未公布的 结果提示，Boritinib对CD8T细胞耗竭有调节作用。在具体目标2中，我们将评估 Th17细胞是Boritinib/炎症小体触发的效应器，导致对耗尽的CD8 T细胞的调制。在……里面 具体目标3我们将研究结合两种疗法时时机的影响。我们推测这一时机 抗PD-1治疗和炎症小体调节的发生可能决定CD8T衰竭的命运 细胞，或许还有免疫治疗方式的临床结果。在此基础上，未来的研究将 在进行临床研究之前，完成正在进行的Boritinib的临床前药理学特征 化合物。这一知识可能使Boritinib成为免疫领域的一流药物的潜在候选者。 肿瘤学。

ABSTRACT Blockade of the immune checkpoint PD-1/PD-L1 has increased overall and progression-free survival in various cancers. However, only a restricted number of patients show clinical benefits. Understanding the mechanisms by which anti-PD-1 antibodies modulate exhausted CD8+ T cells is mandatory to improve this approach. In this context, the role played by inflammation in T cell exhaustion and tumor immunotherapy is controversial. Observations on various mouse models and on human melanoma cohorts support the notion that activation of innate immune players such as inflammasomes, may play a key role in anti-PD-1 therapy. However, we need to identify molecular targets to trigger inflammasome activation potentially leading to improved anti-PD-1 therapy. TMEM176B is an intracellular cation channel strongly expressed by conventional type 2 dendritic cells (cDC2) that inhibits inflammasome activation through ionic mechanisms. Boritinib, a potent TMEM176B inhibitor, induced tumor growth control and reinforced the antitumor activity of anti-PD-1 antibodies in a Tmem176b, inflammasome and CD8+ T cell-dependent manner in lymphoma, melanoma, lung and colon mouse cancer models. However, the mechanism underlying CD8+ T cell reinforcement remains unknown. This project aims at characterizing the mechanisms by which Boritinib improves anti-PD-1 therapy, setting the ground for the clinical evaluation of the compound. Our published and unpublished results led us to propose that inflammasome activation triggered by Boritinib therapy may modulate subsets of exhausted CD8+ T cells, through a mechanism involving Th17 cells. We will carry out a research program involving functional in vivo studies and bioinformatics analysis based on three specific aims. In Specific Aim 1 we wish to confirm and complement our unpublished results suggesting that Boritinib modulates CD8+ T cell exhaustion. In specific aim 2 we will then assess whether Th17 cells are Boritinib/inflammasome-triggered effectors leading to modulation of exhausted CD8+ T cells. In Specific Aim 3 we will study the impact of timing when combining both therapies. We speculate that the timing at which anti-PD-1 therapy and inflammasome modulation occur might determine the fate of exhausted CD8+ T cells and, perhaps, the clinical outcome of immunotherapeutic modalities. On this basis, future research will then complete ongoing preclinical pharmacological characterization of Boritinib before engaging a clinical study of the compound. This knowledge may position Boritinib as a potential candidate to be a first-in-class drug in immuno- oncology.