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的积极参与者。两个最 实体恶性肿瘤中的主要基质成分是免疫细胞和癌症相关的成纤维细胞 （CAFs）。通常，免疫细胞的存在与有利的存活相关，而免疫细胞的存在与有利的存活相关。 CAF与不利的生存相关。虽然B细胞浸润在实体恶性肿瘤中很常见， 它们对生存的贡献尚未得到详细研究。促肿瘤和抗肿瘤功能均已被证实。 这取决于用于检测B细胞的实验系统和标志物。B 不同分化阶段的细胞对肿瘤进展具有相反的作用， 大多数先前的研究使用检测宽范围B细胞亚群的B细胞标记。如果某些B细胞亚群 与肿瘤进展相关，我们假设当肿瘤转移时， 与原发性肿瘤相比。转移瘤通常具有比原发性肿瘤更高的CAF含量。的 B细胞和CAF之间的相互依赖性尚未研究;然而，最近显示， 正常淋巴结中的淋巴样组织成纤维细胞（LOF）调节B细胞向生发中心的募集 （GC）。我们发现CAFs和LOFs具有共同的基因表达谱。这让我们假设 实体瘤中的CAF承担LOF的功能，以募集和阻滞GC期的B细胞， 发育，从而减少功能成熟B细胞的产生。拟定的研究将 使用免疫组织化学方法表征和定量匹配的原发性和转移性卵巢肿瘤中B细胞的组成， - 识别B细胞分化的不同阶段的标志物的组合。功能上的相互依赖 将通过定量CAF影响B细胞的能力来研究共培养物中B细胞和CAF之间的相互作用 募集、存活和分化以及B细胞增强肿瘤细胞的促肿瘤发生特征的能力。 咖啡馆。B细胞和CAF之间的相互依赖性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细胞或CAF的亚群被灭活。 除了探索一个过去受到有限关注的研究领域外， 解决了对更有效的免疫疗法的迫切需求。B细胞疗法在血液病中的成功 恶性肿瘤和自身免疫性疾病以及新的B细胞导向剂的出现重新点燃了 关注B细胞作为实体瘤治疗靶点。然而，更详细地了解不同的B- 细胞亚群及其在肿瘤生长中的作用是选择性消耗促肿瘤B细胞所必需的 亚群和/或控制它们在实体瘤中的平衡。我们的研究将产生一个定量地图的个人 匹配的原发肿瘤和转移瘤中B细胞亚群，阐明CAF在使B- 细胞成熟，并测试CAF功能的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.