Cancer-Associated Fibroblasts Alter the Composition of B cells in Solid Malignancies

肿瘤间质越来越被认为是肿瘤进展过程中的积极参与者。最多的两个 实体恶性肿瘤的主要间质成分是免疫细胞和肿瘤相关的成纤维细胞 (CAF)。通常，免疫细胞的存在与良好的存活率有关，而存在 CAFS与不良生存有关。尽管B细胞浸润性疾病在实体恶性肿瘤中很常见， 它们对生存的贡献还没有得到详细的研究。促肿瘤和抗肿瘤的功能都是 演示取决于用于检测B细胞的实验系统和标记物。B的可能性 处于不同分化阶段的细胞对肿瘤进展的相反作用尚未得到测试 大多数先前的研究使用B细胞标记物来检测广泛的B细胞亚群。如果B细胞的某些亚群 都与肿瘤的进展有关，我们假设当它们在转移中被浓缩时 与原发肿瘤相比。转移性肿瘤的CAF含量通常高于原发肿瘤。这个 B细胞和CAF之间的相互依赖关系尚未被研究；然而，最近的研究表明 正常淋巴结中的淋巴组织者成纤维细胞调节B细胞向生发中心的募集 (GCS)。我们发现CAF和LOF具有共同的基因表达谱。这就引出了我们的假设 实体瘤中的CAF在GC阶段承担LOFS募集和阻断B细胞的功能 发育，从而减少了功能成熟B细胞的产生。拟议的研究将 卵巢原发和转移性肿瘤中B细胞成分的定性和定量 识别B细胞分化不同阶段的标记组合。功能上的相互依赖 将通过量化CAF影响B细胞的能力，在共培养中研究B细胞和CAF之间的关系 B细胞的募集、存活和分化以及增强其促肿瘤特性的能力 CAF。B细胞和CAF之间的相互依赖及其对肿瘤进展的影响将在 几种基因工程小鼠肿瘤模型，其中B细胞亚群或CAF亚群被灭活。 除了探索过去受到有限关注的研究领域外，拟议的研究 解决了对更有效的免疫疗法的迫切需求。血液学中B细胞治疗的成功 恶性肿瘤和自身免疫性疾病以及新的B细胞导向药物的出现重新点燃了人们的热情 对B细胞作为实体瘤治疗靶点的兴趣。然而，更详细地了解不同的B- 选择性去除促肿瘤B细胞需要细胞亚群及其在肿瘤生长中的作用 实体肿瘤中的亚群和/或其平衡的控制。我们的研究将产生一张个人的量化地图 匹配的原发肿瘤和转移瘤中的B细胞亚群，阐明CAF在破坏B-细胞中的潜在作用 细胞成熟和测试CAF功能失活是否可以作为一种新的方法来改善 肿瘤免疫原性。

Tumor stroma is increasingly recognized as an active participant in tumor progression. The two most prominent stromal components in solid malignancies are immune cells and cancer-associated fibroblasts (CAFs). Typically, the presence of immune cells is associated with favorable survival while the presence of CAFs is associated with unfavorable survival. Although B-cell infiltrates are common in solid malignancies, their contribution to survival has not been studied in detail. Both pro- and anti-tumor functions have been demonstrated depending on the experimental system and markers used to detect B cells. The possibility that B cells in different stages of differentiation have opposite effects on tumor progression has not been tested as most prior studies used B-cell markers that detect a broad range of B-cell subsets. If certain subsets of B cells are associated with tumor progression, we hypothesize that they will be enriched in metastases when compared to primary tumors. Metastases typically have a higher content of CAFs than primary tumors. The interdependence between B cells and CAFs has not been studied; however, it has recently been shown that lymphoid organizer fibroblasts (LOFs) in normal lymph nodes regulate B cell recruitment to germinal centers (GCs). We found that CAFs and LOFs share a common gene expression profile. This led us to hypothesize that CAFs in solid tumors assume the function of LOFs to recruit and arrest B cells in the GC-stage of development, thereby diminishing the production of functionally mature B cells. The proposed study will characterize and quantitate the composition of B cells in matched primary and metastatic ovarian tumors using combinations of markers that identify distinct stages of B-cell differentiation. The functional interdependence between B cells and CAFs will be studied in co-cultures by quantitating the ability of CAFs to affect B-cell recruitment, survival, and differentiation as well as the ability of B cells to potentiate pro-tumorigenic features of CAFs. The interdependence between B cells and CAFs and its effect on tumor progression will be tested in several genetically engineered mouse tumor models in which either subsets of B cells or CAFs are inactivated. In addition to exploring a research area that has received limited attention in the past, the proposed study addresses an urgent need for more effective immunotherapies. The success of B-cell therapies in hematologic malignancies and autoimmune diseases and the emergence of new B-cell-directed agents have re-ignited interest in B cells as therapeutic targets in solid tumors. However, a more detailed understanding of different B- cell subsets and their roles in tumor growth are required for selective depletion of the tumor-promoting B-cell subsets and/or control of their equilibrium in solid tumors. Our study will yield a quantitative map of individual subsets of B-cells in matched primary tumors and metastases, clarify the potential role of CAFs in derailing B- cell maturation and test whether inactivation of CAF function could be used as a novel approach to improve tumor immunogenicity.