Role of Tumor-Infiltrating B Cells in Breast Cancer Metastasis

Metastasis continues to be a major clinical problem in breast cancer. The median overall survival of patients with metastasis is only 2.5 years. Therefore, there is an urgent need for developing effective strategies to eradicate metastases to prolong patient survival. It is becoming increasingly clear that metastasis is not only driven by intrinsic changes in the cancer cells but also supported by the non-tumor immune cells in the tumor microenvironment. Our long-term goal is to understand the interactions between the immune system and metastatic cancer cells in order to find new immunotherapeutic targets against metastasis, which is in line with the overarching objectives of the Breast Cancer Research Program and a priority area for Breast Cancer program at Columbia University.

Over the past decade, my research has focused on (i) understanding the immune functions that metastatic cells hijack in order to thrive in foreign tissues and (ii) devising strategies to deplete these critical support systems to eradicate metastatic cells. With our clinical collaborations, we have successfully progressed from our basic science findings to preclinical models and ongoing investigator-initiated trials at the Sloan Kettering Cancer Center. In collaboration with our team of investigators now at Columbia University, our new findings involving tumor-infiltrating B cells brings new opportunities for devising immunotherapy approaches against breast cancer metastasis. Our partnering investigator and team specialize in the field of B cell development and malignancies. Therefore, integrating knowledge from diverse areas of expertise such as B cell biology, pathology, breast cancer oncology, biostatistics, and basic science, we hope to accelerate progress in the area of breast cancer metastasis to prolong survival as part of our goals. The rationale, objectives, and expected outcomes outlined below are designed to combine insights from experimental analysis and clinical validation.

B-lymphocytes circulate and patrol in search of invading antigens as part of normal immune function. As such, the conventional role of B cells in antibody production and humoral immunity is well characterized. However, subsets of B cells can also have a contrasting tumor promoting function in cancer, as demonstrated in skin, prostate, and recently in pancreatic cancers. The discovery of this new role of B cells has drawn attention to this previously overlooked arm of adaptive immunity and initiated new clinical trials in prostate cancer in this direction. However, the contribution of B cells in metastatic breast cancer remains poorly understood and represents an opportunity for targeting breast cancer. Analysis of breast cancer tissues from patients has led us to this new area of tumor-infiltrating immune cells, the area of B-lymphocytes or B cells in breast cancers. We find two insights that formed the framework for this proposal. First, we found that B cell infiltrates are enriched in metastatic lesions in mouse models of breast cancer and that certain B cell subsets (CXCR2+) can promote metastasis in mouse models when co-injected with tumor cells. Second, tumor-infiltrating B cells are also increased in the triple-negative, Stage III subtype of human breast cancers, compared to hormone-positive tumors or adjacent normal, suggesting a tumor-promoting role for these cells in metastatic breast cancer.

The objective of this application is to identify the tumor-promoting subsets of B cells in human breast cancer metastasis and to understand their mechanism of action using mouse models of basal-like or triple-negative breast cancers. The two major goals of this project are: (1) Define the tumor-infiltrating B cell population in human breast cancers and mouse models recapitulating the basal subtype of breast cancer, by RNA profiling of purified B cells from metastatic tissues as prerequisite for the identification of secretory molecules and signaling pathways that may be exploited for prognostication and therapeutic approaches. (2) Dissect the functional role of tumor-infiltrating B cells in metastatic progression in breast cancer in vivo, by using a combination of genetic and pharmacologic approaches in mouse models of breast cancer.

Triple-negative tumors represent one of the most aggressive subtypes of breast cancers with high incidences of metastasis with very few options of effective treatment strategies. Our proposed studies are aimed at developing new opportunities for blocking metastasis by modulating our own immune system. Most immunotherapies are focused on T cell function; however, inhibition of tumor-promoting B cell subsets (e.g., CXCR2+ subset) represents complementary ways of preventing metastatic relapse. We have the prerequisite mouse models in place, human metastasis tissues available for profiling, and experience in identifying targetable pathways in B cells to achieve our goal. Therefore, using these complementary approaches, we anticipate accelerated progress in understanding the role of tumor-infiltrating B cells in metastasis in the short term within the grant period.