Stimulation of the immune system through the use of immunotherapy has proven to be an effective therapeutic to eliminate tumors. However, many patients are unresponsive or develop resistance to immunotherapy, indicating there is still much to be learned about the mechanisms and factors that regulate the immune response within the tumor microenvironment. The two main components of the tumor microenvironment are immune cells (i.e. T cells, B cells, and NK cells) and cancer-associated fibroblasts (CAFs). It is becoming increasingly clear that CAFs play an important role in tumor progression, including influencing the anti-tumor immune response. In order to develop effective cancer therapies, it is imperative to have a complete understanding of the cells involved and the mechanisms regulating the anti-tumor response. CAFs are associated with poor prognosis and have been shown to inhibit the anti-tumor T cell and NK cell response. However, the relationship between CAFs and B cells in the tumor microenvironment is unknown. B cells not only secrete antibodies that can target tumor cells for destruction, but can also present antigens to T cells and secrete various types of cytokines which can influence the anti-tumor immune response in an either pro- or anti-tumorigenic manner. B cells undergo different stages of differentiation before becoming fully functional mature B cells.
Our preliminary results in tumors isolated from ovarian cancer patients show that CAF-rich tumors are associated with abnormally functioning B cells. Additionally, B cells that were co-cultured with CAFs from human ovarian tumors showed decreased capacity to proliferate. This proposal will test the hypotheses that B cells in different stages of differentiation have opposing effects on tumor growth and that CAFs influence the ratio of pro- and anti-tumorigenic B cells. This project will be the first to quantify the differences in B cell populations in patient-matched ovarian primary, metastatic, and recurrent tumors, as well as determine the relationship between CAFs and B cells within the tumor microenvironment. Such information will be crucial for selective targeting of the pro-tumorigenic subsets of B cells and/or promoting their differentiation to enhance the immune response in ovarian cancer patients.
Dr. Marcela Haro is a Postdoctoral Fellow in the laboratory of Dr. Sandra Orsulic at Cedars-Sinai Medical Center Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute in Los Angeles, California. Dr. Haro received her M.S. in Biology from California State University, Los Angeles and her PhD in Immunology from Wake Forest University School of Medicine. Her doctoral studies in the laboratory of Dr. Karen Haas focused on the regulation of protective B cell anti-tumor responses. In 2014 Dr. Haro was awarded an NIH F31 Ruth L. Kirschstein Predoctoral Individual National Research Service Award for her work on PD-1 regulation of protective immune responses to Tn+ tumors. She is also a recipient of the NIH R25 Minority Opportunities in Research Program Bridges to PhD Fellowship. Dr. Haro received the Merinoff World Congress 2014 B-1 Cell Development and Function Travel Award, and was invited to give a presentation as one of the speakers. Dr. Haro’s current research focuses on the interaction of cancer-associated fibroblasts and B cells in ovarian cancer.