______________________________________________________________________________ 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.

Public Health Relevance

_____________________________________________________________________________ Although immunotherapies have demonstrated remarkable efficacy as anti-cancer agents in a subset of patients, it is unclear why the majority of patients are not responsive to immune activation. Successful cancer treatment with immunotherapies requires a precise understanding of the immune cell subsets and mechanisms that control their activation and expansion and recent evidence suggests that B cells can both promote and inhibit tumor progression depending on the signals received from the tumor microenvironment. This project will provide a quantitative map of B-cell subsets in primary and metastatic ovarian cancer and test the bi-directional interaction between B cells and cancer-associated fibroblasts in the tumor microenvironment; results from this project will serve as a foundation for therapeutic targeting of the B-cell-microenvironment interface to enhance tumor immunity.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZCA1-RPRB-M (M1))
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Howcroft, Thomas K
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Cedars-Sinai Medical Center
Los Angeles
United States
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Jia, Dongyu; Nagaoka, Yoshiko; Katsumata, Makoto et al. (2018) Inflammation is a key contributor to ovarian cancer cell seeding. Sci Rep 8:12394
Jia, Dongyu; Liu, Zhenqiu; Deng, Nan et al. (2016) A COL11A1-correlated pan-cancer gene signature of activated fibroblasts for the prioritization of therapeutic targets. Cancer Lett 382:203-214