Anti-tumor Immunity in Myeloma

描述(申请人提供)：肿瘤细胞与微环境(TME)之间的相互作用对骨髓瘤(MM)及其前驱未确定意义的单克隆性伽马病(MGUS)的生物学有重要影响。本应用是我们先前工作的继续，其中我们描述了MM中TME的几个方面。我们先前工作中的一个主题是，MGUS向MM的转变与TME的几个变化有关，失去了抗肿瘤免疫和进行性炎症。在这里，我们将探讨肿瘤细胞的特性与TME变化之间的联系。根据我们的初步研究，我们假设肿瘤细胞分泌WNT抑制剂和髓系细胞的募集在免疫和炎症平衡改变中起主要作用。在目标1中，我们将探讨WNT抑制剂对宿主免疫反应的调节作用。在目标2中，我们将进一步描述髓系细胞和骨髓瘤之间在调节基因组不稳定性方面的串扰。这些研究可能提供几个靶点，以恢复免疫与炎症的失调，并限制这种癌症的基因组不稳定性。 公共卫生相关性：这项工作建立在我们之前的研究基础上，以更好地了解骨髓瘤肿瘤床属性的变化。这些研究可能为控制肿瘤生长和实现持久的治疗反应提供新的方法。

DESCRIPTION (provided by applicant): Interactions between tumor cells and the microenvironment (TME) have a major impact on the biology of myeloma (MM) and its precursor monoclonal gammopathy of undetermined significance (MGUS). This application is a continuation of our prior work wherein we characterized several aspects of TME in MM. A theme from our prior work is that transition of MGUS to MM is associated with several changes in TME, with loss of anti-tumor immunity and progressive inflammation. Herein we will pursue the link between properties of tumor cells and changes in TME. Based on our preliminary studies, we posit that secretion of wnt inhibitors by tumor cells and the recruitment of myeloid cells play a major role in the altered balance of immunity and inflammation. In Aim 1, we will pursue the effect of wnt inhibitors on the regulation of host immune response. In Aim 2, we will further characterize the crosstalk between myeloid cells and myeloma in the regulation of genomic instability. These studies may provide several targets to restore the dysregulation of immunity versus inflammation and restrict genomic instability in this cancer. PUBLIC HEALTH RELEVANCE: This work builds on our prior studies to better understand the changes in the properties of the tumor bed in myeloma. These studies may provide novel approaches to control tumor growth and achieve durable responses to therapy.