PTP1b Inhibition Restores the Innate Anti-tumor Response During Chemotherapy

项目摘要 尽管在诊断和治疗方面取得了进展，但癌症仍是美国第二大死亡原因。 States.适应性免疫检查点（如PD-1和CTLA 4）的发现和靶向是一个布恩 to cancer癌症patients病人.不幸的是，只有一部分患者会有反应，而那些有反应的患者往往会复发。中 为了提高适应性免疫靶向治疗的疗效，已经提出了一些临床试验 或者正在进行中，探索检查点阻断与化疗的结合。的一个理由 联合疗法的另一个优点是化疗诱导免疫原性肿瘤细胞死亡，这提供了稳健的免疫原性肿瘤细胞死亡。 通过释放新抗原和损伤相关分子模式激活抗肿瘤应答 （DAMP），其启动先天性促炎反应。 我们发现并表征了一种新的先天免疫检查点，肿瘤细胞利用这种检查点来抑制肿瘤细胞的增殖。 化疗期间的免疫反应。我们发现肿瘤分泌蛋白结合并激活了 巨噬细胞Mer受体，导致关键Toll样受体（TLR）衔接子表达减少 MyD 88蛋白。在缺乏MyD 88的情况下，巨噬细胞不再能够响应DAMP/TLR信号传导， 有效防止化疗期间的促炎反应。这种抑制机制是 不同来源的肿瘤的特征，包括黑色素瘤、肺癌、胰腺癌和乳腺癌。 我们的机制研究已经确定，配体激活的巨噬细胞Mer诱导三元复合物 形成，增加Mer，Stat 1和称为PTP 1b的磷酸酶的结合。这个复杂 减少Stat 1的磷酸化和核转位，导致MyD 88减少 表情用PTP 1b抑制剂治疗可以阻断这种免疫抑制过程，并恢复DAMP。 介导的体外和体内活化。PTP 1b抑制与化疗联合导致约50% 在多种鼠癌症中的肿瘤生长减少，包括化疗抗性模型。 我们假设，通过靶向Mer：PTP 1b轴，我们可能能够改善先天性， 随后的适应性免疫反应。为了验证我们的假设，我们建议：1） 确定控制Mer配体的肿瘤分泌的调节机制，以及它们在肿瘤细胞中的表达， 人类肿瘤是化疗反应的预测，2）确定哪种形式的化疗效果最好 与PTP 1b抑制相结合的强大免疫激活和3）确定 化疗/PTP 1b抑制联合治疗对适应性免疫应答的影响。

PROJECT SUMMARY Despite advances in diagnosis and treatment, cancer is the second leading cause of death in the United States. The discovery and targeting of adaptive immune checkpoints (like PD-1 and CTLA4) has been a boon to cancer patients. Unfortunately, only a subset of patients will respond and those that do often relapse. In an attempt to improve the efficacy of adaptive immune targeted therapy, several clinical trials have been proposed or are underway, exploring the combination of checkpoint blockade with chemotherapy. One rationale for combination therapy is that chemotherapy induces immunogenic tumor cell death which provides robust activation of the anti-tumor response by releasing neo-antigens and Damage Associated Molecular Patterns (DAMPs) that initiate the innate pro-inflammatory response. We discovered and characterized a novel innate immune checkpoint utilized by tumor cells to suppress the immune response during chemotherapy. We found that tumor secreted proteins bind and activate the macrophage Mer receptor, leading to a reduction in the expression of the key Toll-Like Receptor (TLR) adapter protein MyD88. In the absence of MyD88, macrophages are no longer able to respond to DAMP/TLR signaling, effectively preventing the pro-inflammatory response during chemotherapy. This suppressive mechanism is characteristic of tumors of diverse origins including melanoma, lung, pancreas and breast cancers. Our mechanistic studies have identified that ligand-activated macrophage Mer induces ternary complex formation, increasing the association of Mer, Stat1 and a phosphatase known as PTP1b. This complex reduces the phosphorylation and nuclear translocation of Stat1 which leads to a decrease in MyD88 expression. Treating with a PTP1b inhibitor blocks this immune suppressive process and restores DAMP- mediated activation in vitro and in vivo. Combining PTP1b inhibition with chemotherapy causes ~50% decrease in tumor growth in multiple murine cancers, including chemotherapy resistant models. We hypothesize that by targeting the Mer:PTP1b axis, we may be able to improve the innate, and subsequent adaptive, immune response during chemotherapy. To test our hypothesis we propose to 1) determine the regulatory mechanism governing tumor secretion of Mer ligands and whether their expression in human tumors is predictive of chemotherapy response, 2) identify which forms of chemotherapy yield the most robust immune activation in combination with PTP1b inhibition and 3) ascertain the effects of chemotherapy/PTP1b inhibition combination therapy on the adaptive immune response.