Anti-Tumor immunity in myeloma

描述（由申请方提供）：多发性骨髓瘤是一种无法治愈的B细胞肿瘤，治疗选择有限。我们的目标是研究宿主免疫系统抵抗患者这种肿瘤的能力。在肿瘤前丙种球蛋白病（MGUS）患者中，具有几乎所有已知的骨髓瘤基因组和细胞遗传学变化的转化浆细胞的克隆扩增可在临床上长期保持稳定。我们的初步研究表明，这些患者对瘤床中的肿瘤细胞产生了强烈的特异性免疫反应，而骨髓瘤患者中没有发现这种免疫反应。我们的假设是，宿主免疫应答在控制患者肿瘤细胞的恶性生长中起关键作用，并且这种应答严重依赖于体内肿瘤-树突状细胞-T细胞相互作用的背景。MGUS-骨髓瘤是研究肿瘤-免疫相互作用的特别有用的模型，因为在这种肿瘤中可以直接从骨髓肿瘤床分离肿瘤和免疫效应细胞和抗原呈递细胞，而不需要离体培养和酶处理。我们的长期目标是学会利用宿主免疫反应，以防止MGUS进展为骨髓瘤。我们的具体目标是：1）研究骨髓瘤和MGUS患者血液和瘤床中宿主抗肿瘤CD 4+和CD 8 + T细胞应答的性质; 2）表征瘤床中抗原呈递细胞的性质及其与原位肿瘤细胞的相互作用;以及3）研究肿瘤细胞的特定亚群是否可以特异性地靶向树突细胞，树突细胞是人体的天然佐剂。这些研究将提供关于肿瘤微环境中肿瘤细胞与免疫系统之间相互作用的新信息;并提出针对树突状细胞增强患者抗肿瘤免疫的新策略。

DESCRIPTION (provided by applicant): Multiple myeloma is an incurable B cell tumor with limited treatment options. Our goal is to study the ability of the host immune system to resist this tumor in patients. Clonal expansion of transformed plasma cells with nearly all of the known genomic and cytogenetic changes found in myeloma can remain clinically stable for prolonged periods in patients with preneoplastic gammopathy (MGUS). Our preliminary studies suggest that these patients mount a vigorous and specific immune response against tumor cells in the tumor bed, which is not found in myeloma patients. Our hypothesis is that the host immune response plays a key role in controlling the malignant growth of tumor cells in patients, and this response is critically dependent on the context of tumor-dendritic celI-T cell interactions in vivo. MGUS-myeloma is a particularly useful model to study tumor-immune interactions, as it is possible in this tumor to isolate tumor and immune effector and antigen presenting cells directly from the bone marrow tumor bed, without the need for ex vivo culture and enzymatic treatments. Our long-term goal is to learn to harness the host immune response in an attempt to prevent progression of MGUS to myeloma. Our specific aims are 1) to study the nature of host anti-tumor CD4+ and CD8+ T cell response in the blood and tumor bed of patients with myeloma and MGUS; 2) to characterize the nature of antigen-presenting cells in the tumor bed and their interactions with tumor cells in situ; and 3) to study whether specific subpopulations of tumor cells can be specifically targeted to dendritic cells, the body's natural adjuvant. These studies should provide novel information about the interactions between tumor cells and immune system in the context of tumor microenvironment; and suggest novel strategies to boost anti-tumor immunity in patients targeting dendritic cells.