Targeting Immunosuppressive Alterations in the Tumor Microenvironment Resulting from Therapy-Induced DNA Damage Responses
Abstract
Scientific Objective and Rationale: Though new effective therapies for prostate cancer have been developed in recent years, chemotherapy and radiation remain widely used in the treatment of localized and metastatic disease. In addition, efforts to improve anti-tumor immune responses have also proven beneficial in subsets of patients. Acquired resistance to current therapies accounts for treatment failure in more than 95% of patients with metastatic prostate cancer. It is known that normal cells that surround tumor cells, collectively termed the tumor microenvironment (TME), can greatly influence responses to prostate cancer therapies as well as how the immune system recognizes and eradicates tumors. During treatment, chemotherapy and radiation not only target tumor cells but also damage the normal cells in the surrounding TME. These benign cells respond with a damage response capable of influencing the immune system, both within a tumor mass as well as systemically to alter immune responses in distant metastatic sites. This proposal aims to identify key factors and mechanisms that drive this process in order to enhance anti-tumor immunity. Principal Investigator s Goals in Prostate Cancer Research: My long-term career objective is to direct a research group that improves the understanding of interactions between the TME, tumor cells, and host immune system, which will lead to the development of better treatment strategies for prostate cancer. The studies contained in this proposal will allow me to further develop my research skills for conducting critical, innovative, and impactful studies that are supported by strong basic science. Additionally, the training component of this plan includes both technical and formal instruction in the areas of cancer pathology/histology, biostatistics, grant writing, genetics, research ethics, and tumor immunology as well as providing opportunities to establish collaborations with others in the field and supervise and train interns and technicians. Applicability of Research: The successful performance of this project will provide a better understanding of how tumors avoid the immune system and outline an opportunity for improving immune-based treatments for men suffering from both localized and specifically, advanced prostate cancer. Developing tumor-directed immune responses represents an important therapeutic opportunity. Major efforts are underway to understand how to improve tumor cell killing within the complex microenvironment of a tumor. Our studies have shown that cancer treatments may also produce an immune suppressive microenvironment that could block effective immune attack. The aims of this project are to (1) identify the changes in the immune landscapes (composition and function) that result from cancer treatments; (2) determine the influence of treatment-induced factors on key aspects of anti-tumor immune function; and (3) determine if blocking these treatment-induced factors will improve the effectiveness of immune-mediated eradication of prostate cancer cells. Contributions to the Field of Prostate Cancer Research: This study has the potential to reveal new avenues of immune-based therapies for individuals suffering advanced prostate cancer, as well as more clearly characterize the mechanism by which the TME affects treatment resistance in the context of immune suppression.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610228
Entities
People
- Wei Jin
Organizations
- Fred Hutchinson Cancer Center
- United States Army