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Immune Networks in Breast Cancer

Project:  Immune Networks in Breast Cancer

Principal Investigator - Michael Campbell

ABSTRACT

Breast cancer is a complex disease.  Its etiology is likely multifactorial, its development can span decades, and its clinical course is quite variable.  Just as complex as the disease itself, is the role of the immune system in the development or control of breast cancer.  Indeed, the immune system may be a two-edged sword.  On one edge, anti-tumor immune responses have been shown to play a role in preventing tumor growth and spread.  On the other, some host immune reactions may serve to facilitate cancer development via the production of cytokines/growth factors that enhance tumor growth, either directly or indirectly by suppressing beneficial anti-tumor immune responses.  It is becoming apparent that no single mechanism can explain the phenomenon of immunological rejection or immune enhancement of a tumor. The contribution of several components of innate and adaptive immune responses is likely to be involved.  Thus, examination of both edges of the sword may reveal immunological markers of risk, as well as potential targets for interventions.

Since peripheral blood mononuclear cells (PBMC) circulate throughout the body, they may serve as a sensitive indicator/monitor of disease as well as a barometer of response to therapy.  In previous work, we have shown that women with breast cancer have alterations in T cell and monocyte/macrophage populations in their peripheral blood.  These studies utilized multi-color flow cytometry techniques.  However, due to the limited number of stains that can be used per sample, it’s not possible to identify complex immune signaling network interactions using this technique.  To expand on this previous work, we propose to further characterize breast cancer associated immune signaling networks using mass cytometry. Standard flow cytometry, which uses fluorophore-tagged antibodies, is typically limited due to overlap of emission spectra. As the number of fluorphores increases, the substantial overlap into neighboring detection channels requires significant compensation.  In contrast, mass cytometry uses mass tags rather than fluorphores, with measurement of the tags using an inductively coupled plasma mass spectrometer.  The high resolution of the mass spectrometer and the large dynamic range eliminates the need for compensation.  The large number of available mass tags (potentially greater than 100) allows for massively multiplexed analyses.  In addition, the reagents are stable and insensitive to light, so experiments can be performed then stored and/or shipped for analysis (fluorphore activity rapidly decreases with light exposure and over time). 

The analysis of immune signaling profiles using highly multiplexed mass cytometry analyses can identify and mechanistically define populations of cells and potential interaction networks that would be difficult, if not impossible, to identify via fluorescence-based flow cytometry.  In this pilot study we will develop and compare peripheral blood and breast tissue immune signaling network profiles from women with breast cancer and healthy women.  We will also determine if immune signaling networks in the peripheral blood of women with breast cancer reflect the immune microenvironment of the breast tumor tissue.  The identification of aberrant immune signaling profiles (peripheral blood or tissue-based) could lead to new biomarkers of disease and/or novel targets for therapeutic intervention.