BALANCING PROTUMOR AND ANTITUMOR IMMUNITY TO CONTROL BREAST CANCER METASTASIS

Project: Research project

Project Details

Description

Background: While current standards of treatment for breast cancer have greatly improved patient morbidity and mortality, the fact that 40% of patients still succumb to the disease underscores the need for improved treatment strategies. There is compelling evidence to suggest that breast cancer dissemination is an early event, and metastases emerge from latent tumor cells that remain dormant at disseminated sites for many years. Identifying mechanisms regulating the switch from dormancy to proliferative metastatic growth has been elusive due to the lack of testable concepts and suitable experimental models. One preferred niche for breast cancer cells is the bone marrow where both tumor cells and tumor-specific memory T cells are readily detected. Persistence of memory T-cells requires continuous stimulation by cognate antigen, and provides independent evidence for host immune response to the tumor. A new discovery that has profound impact on the cancer field is the revelation that the host immune response is 'partner in crime' with the tumor. It is now understood that many of the same innate and adaptive mechanisms that respond to tissue injury play an essential role in shaping the tumor microenvironment that both nurtures the tumor and is a potent force in suppressing protective T cells. The emerging picture is that the outcome of cancer is determined by the balance between anti-tumor and pro-tumor immunity.Objective: We hypothesize that transition to metastatic growth requires a shift in balance from protective TH1 to pro-inflammatory (TH17) response, and that this shift is STAT3 dependent. Interception of this pathway is predicted to prevent and perhaps cure bone disease, preventing further metastasis.Specific Aims:1) Test the hypothesis that tumor cell lines with high metastatic potential are, in comparison with low metastatic tumors, more competent in mobilizing inflammatory cells.2) Test the hypothesis that STAT3 signaling and IL-23 play critical roles in the cross talk between tumor cells and infiltrating cells, shaping a receptive and nurturing inflammatory microenvironment for breast cancer to progress.3) Test the hypothesis that natural defense mechanisms are sufficient to control transition from 'dormancy' to bone disease, while high-fat diet, a recognized risk factor in breast cancer, can tilt the balance from a protective TH1 to a pathogenic pro-inflammatory immune response.Study Design: We use a unique syngeneic mouse model of breast cancer metastasis model that consists of the orthotopic transplantation in the mammary gland of a number of closely related breast epithelial cell lines with high (TM40D-MB), low (TM40D), or no (TM6) metastatic potential. The tumors are genetically modified to express the influenza hemaglutinin fused to Green Fluorescence Protein (HA-GFP), which acts as marker to detect both the cells and the immune response to the tumor. We have shown that the tumor cells readily migrate to the bones and form either metastases or a state of tumor dormancy, depending on the cells used. We will transfer HA-specific T-cells from T-cell receptor transgenic mice to tumor-bearing mice. This will allow us to follow T-cell responses to the primary tumor and the bone marrow disseminated tumor cells. It will also allow us to study the impact of these T cells on the tumor microenvironment in the bone. We will focus on CD4+ HA specific T-regulatory cell and helper T cells, and how these interact with the innate immune response to produce or control cancer associated inflammation. We hypothesize that bone metastasis is promoted by a STAT3 and IL23 driven inflammatory pathway. We will test whether this pathway is a suitable therapeutic target for immune therapy of breast cancer metastasis.Innovation: The major innovation is the idea of stopping breast cancer metastasis in the bone by manipulating the interplay between pro- and anti-tumor immunity. Since the birth of tumor immunology in 1909, the goal of cancer eradication through vaccines has remained elusive largely due to our incomplete understanding of how the immune system works. Recent insights have revived hopes for the design of rational treatment strategies. There is now clear and unequivocal evidence suggesting that breast cancer evokes protective immune responses, while it harnesses inflammatory reactions to progress. Successful immune therapy of cancer needs to take into account both arms of the immune response. By focusing on the interplay between tumor and immune cells in the bone, our findings could provide vital information for hindering breast cancer progression.Impact: Cellular immunology arguably could provide the most targeted approach for eradicating disseminated tumor cells. This is because immune cells can destroy the tumor, or aid tumor survive and progression. Understanding the interplay between the two opposing functions is the key for designing effective therapies.

StatusFinished
Effective start/end date1/1/099/30/13

Funding

  • Congressionally Directed Medical Research Programs: $419,376.00
  • U.S. Department of Defense: $419,376.00

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