Innate and Adaptive Anti-Myeloma Immunity

骨髓环境中的细胞成分支持多发性骨髓瘤(MM)细胞的生长、存活、迁移和耐药性，既直接通过细胞-细胞相互作用，也间接通过产生可溶性因子。这种微环境的一个关键组成部分是免疫细胞。在之前的授予期间，我们已经在未确定意义的单克隆性伽马病(MGUS)和MM患者中证明了抗原特异性抗MM T和B细胞反应，尽管这些反应可以影响抗MM。 在体外，它们具有细胞毒性，但无法阻止疾病的进展。虽然肿瘤诱导多发性骨髓瘤患者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多发性骨髓瘤免疫反应的发展。我们的初步数据表明，介导这种免疫抑制的机制包括：诱导功能失调的T调节细胞；无效的抗原提呈；可溶性MICA诱导的NKG2D功能抑制，以及与NKG2D和TH17通路相关的过量促炎细胞因子的产生。基于这些数据，我们假设骨髓微环境调节对NKG2D功能障碍的免疫反应和TH17通路，以支持肿瘤进展和抑制抗MM免疫反应的发展。我们在项目2中的目标是识别和靶向调节自身抗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，以改善免疫反应和抑制骨髓瘤细胞生长。为了达到这一目标，我们提出了以下具体目标： 阐明NKG2D通路在MM发病机制中的作用(特异性目标1)；评价TH17通路及其相关的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(特异性目标2)；通过动物模型评价针对NKG2D和TH17通路的新疗法在体外和体内的作用，作为未来I/II期临床试验的前奏(特异性目标3)。这些研究将为改善骨髓瘤的免疫功能和实现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.