Characterization of Tumor Immunobiological Factors that Promote Lymphovascular Invasion and Dissemination in Locally Advanced Breast Cancer
Abstract
Many lethal breast cancers, which initially appear to be localized, spread throughout the body by first gaining access to lymph vessels, a process called lymphovascular invasion (LVI). A particularly prominent example of LVI is the highly aggressive subtype, inflammatory breast cancer (IBC), which irrespective of the hormonal status/molecular subtype grows rapidly as clumps of tumor cells within lymph vessels in the skin of the breast. Although the lymphatics should be a site where the cancer would be exposed to, and attacked by, the immune system, instead IBC cells evade the killer T cells and spread outside the breast. How the IBC cells avoid being killed by the immune system is not well understood, but we have found that a protein that is highly active in IBC, called XIAP (X-linked inhibitor of apoptosis protein) not only helps keep the IBC cells alive, but makes them resistant to killing by T cells. XIAP also activates another protein called NFkappaB, which causes the IBC cells to grow rapidly and to secrete molecules that cause certain cells capable of suppressing the killer T cells to accumulate in the tumor. Our goal is to determine whether this resistance to killing by T cells and suppression of T cell killing function account for the aggressive growth and metastases of breast cancers with LVI such as IBC (taken into account differences in molecular subtypes like triple-negative or HER2 overexpression). We will first confirm that breast cancers with LVI do have these features of resistance to immune-mediated killing and suppression of T cells. We will then test whether factors secreted by these tumors can suppress the growth and function of the killer T cells and finally, will show that T cells exposed to IBC cells cannot destroy the tumor clusters in which IBC grows using innovative models that we have developed to study breast cancer cell aggressive characteristics and lymphatic invasion. By completing this research project, we anticipate identifying tests to predict which localized breast cancers will be able to spread to the rest of the body through the lymph vessels and also finding targets for treatments that can interfere with this mechanism of cancer spread, especially for people with the highly lethal IBC. Because drugs are already available to increase the effectiveness of killing by T cells (such as anti PD-1 antibodies) and are also in development to target XIAP (Smac mimetics) and NFkappaB, we will be poised to translate the findings of this proposal rapidly into human clinical trials.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710297
Entities
People
- Gayathri R Devi
Organizations
- Duke University
- United States Army