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

癌症相关成纤维细胞改变实体恶性肿瘤中 B 细胞的组成

基本信息

批准号：
10213442
负责人：
SANDRA ORSULIC
金额：
$ 35.69万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10213442
关键词：
Address Affect Antineoplastic Agents Area Attention Autoimmune Diseases B cell differentiation B cell therapy B-Cell Development B-Cell Neoplasm B-Lymphocyte Subsets B-Lymphocytes Bone Marrow Cell Maturation Cells Clinical Coculture Techniques Colon Carcinoma Color Complement Factor B Development Equilibrium Fibroblasts Flow Cytometry Foundations Gene Expression Profile Genes Genetically Engineered Mouse Hematologic Neoplasms Hematopoietic Homeostasis Homing Immune Immune system Immunohistochemistry Immunotherapy Impairment In Vitro Individual Lymphoid Malignant Neoplasms Malignant neoplasm of ovary Maps Mature B-Lymphocyte Memory B-Lymphocyte Modeling Mus Neoplasm Metastasis Outcome Ovarian Participant Patients Plasma Cells Play Primary Neoplasm Production Research Role Signal Transduction Solid Solid Neoplasm Source Stromal Cells Structure Structure of germinal center of lymph node System T-Lymphocyte Testing Transforming Growth Factors Tumor Immunity Tumor Promotion Wild Type Mouse cancer biomarkers cancer therapy cancer type cytokine experimental study genetic signature immune activation immunogenicity immunoregulation improved in silico in vivo interest large cell Diffuse non-Hodgkin&apos s lymphoma lymph nodes lymphoid organ lymphoid structures malignant breast neoplasm metastatic colorectal novel strategies outcome forecast ovarian neoplasm patient subsets recruit success therapeutic target tumor tumor growth tumor microenvironment tumor progression tumor xenograft tumorigenic

项目摘要

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.

肿瘤基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成纤维细胞（CAF）。通常，免疫细胞的存在与有利的生存相关，而免疫细胞的存在与 CAF 与不利的生存相关。尽管 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。具有促肿瘤和抗肿瘤功能证明取决于用于检测 B 细胞的实验系统和标记。 B的可能性不同分化阶段的细胞对肿瘤进展具有相反的影响尚未经过测试大多数先前的研究使用 B 细胞标记来检测广泛的 B 细胞亚群。如果 B 细胞的某些亚群与肿瘤进展相关，我们假设它们在转移时会富集与原发肿瘤相比。转移瘤通常比原发肿瘤具有更高的 CAF 含量。这 B 细胞和 CAF 之间的相互依赖性尚未被研究；然而，最近的研究表明正常淋巴结中的淋巴组织成纤维细胞 (LOF) 调节 B 细胞募集至生发中心（GC）。我们发现 CAF 和 LOF 具有共同的基因表达谱。这导致我们假设实体瘤中的 CAF 承担了 LOF 的功能，在 GC 阶段招募和阻滞 B 细胞发育，从而减少功能成熟 B 细胞的产生。拟议的研究将使用以下方法对匹配的原发性和转移性卵巢肿瘤中 B 细胞的组成进行表征和定量识别 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定量 CAF 影响 B 细胞的能力，在共培养中研究 B 细胞和 CAF 之间的关系募集、存活和分化以及 B 细胞增强促肿瘤特征的能力 CAF。 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 细胞亚群或 CAF 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。 B细胞疗法在血液学领域的成功恶性肿瘤和自身免疫性疾病以及新的 B 细胞靶向药物的出现重新点燃了对 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- 细胞亚群及其在肿瘤生长中的作用是选择性消除促肿瘤 B 细胞所必需的实体瘤中的子集和/或平衡控制。我们的研究将得出个体的定量图匹配的原发肿瘤和转移瘤中的 B 细胞亚群，阐明了 CAF 在使 B 细胞脱轨中的潜在作用细胞成熟并测试 CAF 功能失活是否可以作为改善细胞成熟的新方法肿瘤免疫原性。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Are Epithelial Ovarian Cancers of the Mesenchymal Subtype Actually Intraperitoneal Metastases to the Ovary?

DOI：
10.3389/fcell.2020.00647
发表时间：
2020-07-17
期刊：
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
影响因子：
5.5
作者：
Hu, Ye;Taylor-Harding, Barbie;Orsulic, Sandra
通讯作者：
Orsulic, Sandra

DOI：
10.1016/j.canlet.2016.09.001
发表时间：
2016-11-28
期刊：
CANCER LETTERS
影响因子：
9.7
作者：
Jia, Dongyu;Liu, Zhenqiu;Deng, Nan;Tan, Tuan Zea;Huang, Ruby Yun-Ju;Taylor-Harding, Barbie;Cheon, Dong-Joo;Lawrenson, Kate;Wiedemeyer, Wolf R.;Walts, Ann E.;Karlan, Beth Y.;Orsulic, Sandra
通讯作者：
Orsulic, Sandra

Editorial: The Tumor Microenvironment: Recent Advances and Novel Therapeutic Approaches.