Collapsing the Tumor-Supportive Immune Portfolio of Breast Cancer to Achieve Durable Reduction of Metastasis
Abstract
Through studies proposed in this application, we will address the overarching challenge of eliminating the mortality associated with metastatic breast cancer. Metastasis: The most deadly attribute of breast cancer cells is their ability to leave their initial site of growth, travel to discontiguous secondary sites, and proliferate into macroscopic masses. While survival rates are at an all-time high for breast cancer that is localized or regionally advanced, for patients with advanced or metastasized breast cancer, the 5-year survival rate remains at only 26%. This disparity in survival between early- and late-stage breast cancer represents the principal obstacle in breast cancer management. Cancer cells interact with the “stromal” cells in their surrounding and adapt to their environment, a niche commonly referred to as the “tumor microenvironment.” Interactions between tumor cells and the associated stroma represent a powerful relationship that influences the establishment and prognosis of the breast cancer patient. The stromal cells include endothelial cells (that are the source of blood vessels), lymphatic vessels, fibroblasts, and a variety of immune cells. The immune cells are involved in mounting an immune response against the tumor cells. Cancer immunosurveillance involves intricate interplay between “first responder (innate)” and “effector (adaptive)” immune cells. Innate immune cells are important for programming the adaptive immune system to eliminate the tumor. Tumor cells co-opt the immune system and modulate their own niche to create an immunosuppressive, tumor-promoting environment. Macrophages are cells of the innate immune system that present the adaptive immune system with signals that can enable the adaptive cells to launch an immune attack to eradicate the tumor. Tumor cells reprogram macrophages such that macrophages end up fostering growth of the tumor rather than pioneering tumor elimination. Acknowledging the critical role of the immune system in cancer, cancer immunotherapy is now an important treatment option for many cancers, including breast cancer. Given the profound influence of the microenvironment, it is proposed that re-calibration of stromal (immune) cells may be an effective strategy for treating cancer. Thus, while the tumor stroma imparts strong influences on disease progression, it also presents with a therapeutic opportunity that lies in the pliancy of the tumor stroma. The previous Breakthrough Award made it possible for us to pursue studies on understanding how the Hedgehog (Hh) signaling pathway enables a dialog between breast tumor cells and macrophages. We used Vismodegib, a Food and Drug Administration (FDA)-approved, orally bioavailable, pharmacological inhibitor of the Hh pathway, and established a new concept that breast cancer cells mediate a “conversation” or a crosstalk with the tumor-infiltrating macrophages via Hh ligands that act as “conversational” molecules; and this results in immense molecular changes in macrophages that functionally recalibrates them to an immunosuppressive, tumor-promoting state. During these Level 1 studies, we also made the unexpected, yet striking observation that inhibiting Hh signaling altered the T cell portfolio – this was characterized by an increase in activated T cells and a decrease in immunosuppressive T cells, including regulatory T cells (Tregs) and Th2 cells. As such, our findings framed the possibility that inhibition of Hh signaling may restore T cell functions in the breast tumor microenvironment. In this Breakthrough Expansion application, our objectives are (i) to investigate how Hh signaling regulates T cell function in breast cancer and (ii) to test if Hh inhibition collapses the tumor-supportive immune portfolio of hormone and growth receptor expressing breast cancer and if this strategy enables a durable reduction of metastasis. This is important given the fact that 75%-80% of diagnosed breast canc
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910755
Entities
People
- Lalita A. Shevde
Organizations
- United States Army
- University of Alabama at Birmingham