CD28-mediated Regulation of Multiple Myeloma Cell Proliferation and Survival

多发性骨髓瘤（MM）是骨髓（BM）驻留长寿命浆细胞（LLPC）的肿瘤， 占所有血液恶性肿瘤的20%，仅次于非霍奇金淋巴瘤。尽管有新 尽管使用化疗药物，MM仍然是不可治愈的。虽然最初对化疗敏感，但原发性 治疗失败的原因是进展性更难治性疾病的发展， 抗性是由于促存活机制的上调。从而确定了 骨髓瘤细胞存活/耐药性对于开发骨髓瘤的治愈性治疗方法至关重要。 毫米现在清楚的是，骨髓瘤细胞严重依赖于与BM微环境（ME）的相互作用。 对于它们的生存，就像它们正常的LLPC对应物一样，这些相互作用在MM中起着重要作用。 对化疗的抵抗力。尽管它们在骨髓瘤生存中至关重要，但是， 参与这些相互作用的分子和细胞组分的特征仍然很差。在我们最初的 因此，我们假设CD 28在骨髓瘤中发挥重要的促生存作用。虽然 主要被表征为参与T细胞活化的原型T细胞共刺激受体， CD 28也在正常PC和MM上表达。在上一个资助周期完成的工作 表明CD 28通过两个下游信号通路的激活在细胞凋亡中起重要作用。 正常LLPC和MM细胞存活，且治疗性阻断CD 28活化导致MM细胞 在临床前体内模型中对化疗的死亡/再敏感。根据这些调查结果和初步 临床疗效的证据，我们刚刚开始了一项II期临床试验， 难治性/复发性MM（NCT 02334865）最近，我们发现CD 28活化实质上 增强MM细胞的代谢适应性，这在其促存活效应中起主要作用。除了 直接支持MM存活，我们发现MM CD 28也调节MM ME。 其配体CD 80和CD 86在基质树突状细胞（DC）上的表达启动了CD 80/CD 86“反向信号传导”， DC产生促MM存活细胞因子IL-6和免疫抑制性色氨酸（Trp）分解代谢 吲哚胺2，3双加氧酶（IDO）。我们还表明，MM细胞上表达的CD 86具有 独立的促生存功能。最近，我们已经确定犬尿氨酸（Kyn，由IDO生产） Trp的降解）是芳烃受体（AhR）的内源性配体，并且AhR活化具有与受体（Trp）的活性相关的活性。 重要的，但以前未被承认的亲生存的作用，在MM。本建议的具体目标是：1）。 在一项2期临床试验中表征阻断CD 28活化对骨髓瘤化疗耐药性的影响， MM患者，2）。定义CD 28活化如何增强骨髓瘤细胞的代谢适应性，以及3）。 确定MM CD 28介导的DC调节在BM ME中支持MM存活的作用。

Multiple myeloma (MM) is a neoplasm of bone marrow (BM) resident long-lived plasma cells (LLPC) that comprises 20% of all hematologic malignancies - second only to non-Hodgkin’s lymphoma. Despite new chemotherapeutic agents, MM remains incurable. Although initially sensitive to chemotherapy, the primary cause of treatment failure is the development of progressively more chemo-refractory disease whose resistance is due to upregulation of pro-survival mechanisms. Thus defining the specific mechanisms of myeloma cell survival/drug resistance is essential for the development of curative treatment approaches in MM. It is now clear that myeloma cells are critically dependent on interactions with BM microenvironment (ME) for their survival, just like their normal LLPC counterparts, and these interactions play a major role in MM resistance to chemotherapy. Despite their central importance in myeloma survival however, the specific molecular and cellular components involved in these interactions remain poorly characterized. In our original proposal, we hypothesized that CD28 was playing significant pro-survival role in myeloma. Although it has been primarily characterized as the prototype T cell costimulatory receptor involved in T cell activation and survival, CD28 is also expressed on normal PC and MM. Work accomplished during the last funding cycle has demonstrated that CD28 activation through two downstream signaling pathways plays an essential role in the survival of both normal LLPC and MM cells, and that therapeutically blocking CD28 activation leads to MM cell death/resensitization to chemotherapy in preclinical in vivo models. Based on these findings and initial evidence for clinical efficacy, we have just opened a phase II clinical trial of blocking CD28 activation in refractory/relapsed MM (NCT02334865) More recently, we have found that CD28 activation substantially enhances the metabolic fitness of MM cells, which plays a major role in its pro-survival effect. In addition to directly supporting MM survival, we have found that MM CD28 also modulates the MM ME. CD28 engagement of its ligands CD80 and CD86 on stromal dendritic cells (DC) initiates CD80/CD86 “backsignaling” that induces DC production of the pro-MM survival cytokine IL-6 and the immunosuppressive tryptophan (Trp)-catabolizing enzyme indoleamine 2, 3 dioxygenase (IDO). We have also shown that CD86 expressed on MM cells has independent pro-survival function. More recently we have determined that kynurenine (Kyn, produced by IDO degradation of Trp) is an endogenous ligand for the aryl-hydrocarbon receptor (AhR), and AhR activation has a significant but previously unrecognized pro-survival role in MM. The Specific Aims of this proposal are: 1). Characterize the effect of blocking CD28 activation on myeloma chemoresistance in a Phase 2 clinical trial in MM patients, 2). Define how CD28 activation enhances the metabolic fitness of myeloma cells, and 3). Determine the role of MM CD28-mediated modulation of DC in the BM ME in supporting MM survival.