Sculpting Antitumor Immunity as an Approach to Treat Metastatic Breast Cancer
Abstract
We will address the overarching challenge of eliminating the mortality associated with metastatic breast cancer. 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 at the site of the secondary organ, 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 outcomes of breast cancer metastasis and patient prognosis. 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 an intricate interplay between the “first responder (innate)” and “effector (adaptive)” immune cells. The 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 can reprogram macrophages such that the macrophages end up fostering the 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-education of stromal (immune) cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Thus, while the tumor stroma imparts strong influences on disease progression, they also present with a therapeutic opportunity that lies in the pliancy of the tumor stroma. Since the microenvironment is capable of adapting to tumor cells, re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. We propose to immunoedit anti-tumor immunity as an approach to treat breast cancer metastases. We will take advantage of immune cell plasticity by re-educating immune cells to treat cancer rather than targeting just tumor cells or stromal cells for ablation. We have identified that inhibiting the Hedgehog (Hh) signaling pathway re-programs mammary cancer-associated tumor-promoting macrophages to tumor-killing macrophages. We plan to use two distinct immunocompetent mouse model systems to query an approach of chemo-immunotherapy to treat metastatic (mammary) breast cancer. As such, we will undertake studies to (i) interrogate if Hedgehog inhibition is an approach to re-educate the immune system to eliminate breast cancer metastases and (ii) elucidate the mechanism by which Hh/GLI inhibition impacts innate and adaptive immune cells. Our goal is to develop strategies to treat metastatic breast cancer. We have designed our preclinical studies that will enable us to specifically simulate a patient with metastasis. Impact on the patient with metastasis: With the prospects of immunotherapy yielding much optimism in breast cancer, our proposed investigations are designed to investigate the next frontier of comprehensively reprogramming the innate and adaptiv
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810036
Entities
People
- Lalita A. Shevde
Organizations
- United States Army
- University of Alabama at Birmingham