Innate and Adaptive Anti-Myeloma Immunity

BM环境的细胞组分直接通过细胞-细胞相互作用以及间接通过产生可溶性因子支持多发性骨髓瘤（MM）细胞生长、存活、迁移和耐药性。这种微环境的一个关键组成部分是免疫细胞。在之前的授权期间，我们已经证明了具有未确定意义的单克隆丙种球蛋白病（MGUS）和MM患者的抗原特异性抗MM T和B细胞应答。 在体外细胞毒性中，它们不能阻止疾病进展。虽然MM患者中肿瘤诱导的免疫功能障碍的机制尚不清楚，但我们的初步数据表明，肿瘤细胞可以抑制有效的抗MM免疫应答的发展。我们的初步数据表明，介导这种免疫抑制的多种机制包括：诱导功能失调的T调节细胞;无效的抗原呈递;可溶性云母诱导的NKG 2D功能抑制，以及产生与NKG 2D和TH 17通路相关的过量促炎细胞因子。基于这些数据，我们假设BM微环境调节对NKG 2D功能障碍和TH 17通路的免疫应答，以支持肿瘤进展并抑制抗MM免疫应答的发展。我们在项目2中的目标是识别和靶向调节自体抗MM反应的细胞和可溶性因子，以开发有效的策略来标记这些途径，以改善免疫反应并抑制骨髓瘤细胞生长。为了实现这一目标，我们提出以下具体目标： 阐明NKG 2D通路在MM发病机制中的作用（具体目标1）;评价TH 17通路和相关促炎细胞因子在促进MM免疫功能障碍和肿瘤生长中的作用（具体目标2）;使用动物模型在体外和体内评价靶向NKG 2D和TH 17通路的新型疗法的作用，作为未来I/II期临床试验的前奏（具体目标3）。这些研究将为改善免疫功能和实现骨髓瘤抗肿瘤反应提供框架。

The cellular components of the BM milieu support multiple myeloma (MM) cell growth, survival, migration and drug resistance, both directly by cell-cell interactions as well as indirectly by production of soluble factors. A key component of this microenvironment is immune cells. During the previous granting period, we have demonstrated antigen specific anti-MM T and B cell responses in patients with monoclonal gammopathy of undetermined significance (MGUS) and MM. Although these responses can affect anti-MM cytotoxicity in vitro, they fail to impede disease progression. While the mechanisms governing tumor-induced immune dysfunction in MM patients are unknown, our preliminary data suggests that tumor cells can inhibit the development of an effective anti-MM immune response. Our preliminary data suggests a number of mechanisms mediating this immune inhibition including: induction of dysfunctional T regulatory cells; ineffective antigen presentation; soluble MICA induced suppression of NKG2D function, and production of excessive pro-inflammatory cytokines associated with NKG2D and TH17 pathways. Based upon these data, we hypothesize that the BM microenvironment modulates the immune responses towards NKG2D dysfunction and TH17 pathways to support tumor progression and inhibit the development of anti-MM immune responses. Our goal in Project 2 is to identify and target cellular and soluble factors modulating autologous anti-MM responses to develop effective strategies tageting these pathways to improve immune responses and inhibit myeloma cell growth. To achieve this goal, we propose the following Specific Aims: to elucidate the role of the NKG2D pathway in MM pathogenesis (Specific Aim 1); to evaluate the role of TH17 pathway and associated pro-inflammatory cytokines in promoting immune dysfunction and tumour growth in MM (Specific Aim 2); to evaluate the role of novel therapies targeting NKG2D and TH17 pathway in vitro and in vivo using animal models as a prelude to future phase I/II clinical trials (Specific Aim 3). These studies will provide the framework to improve immune function and to achieve anti-tumor responses in myeloma.