Functions of IL-1alpha and ESE-1 in Reactive Stroma Modulation of the Immune Landscape in Prostate Cancer
Abstract
Scientific Rationale: Immune therapy for the treatment of cancer has made several advances; however, many patients respond poorly or not at all. Mechanisms for different responses to this therapy are not understood. Considerable evidence now shows that tumors have an immune-suppressive biology that effectively suppresses the immune system. The immune suppression within a tumor has become the target for immune therapy approaches, which attempts to inhibit the immune suppression and therefore allows the patient’s own immune system to destroy cancer cells. Cells termed carcinoma-associated fibroblasts (CAFs) grow with prostate cancer cells and become a part of the tumor. These cells have been shown to have high immune suppressive biology. Accordingly, it is possible that the CAFs within a tumor function to alter immune cell recruitment to the tumor and enhance the immune suppression. The dilemma is that we do not know where CAF cells originate, how the CAF cells are activated, and what factors they make that likely promotes immune suppression within the tumor. It is possible that patients who do not respond to immune therapy have key differences in the makeup and biology of CAFs in their tumors. Hence, it is important to understand the mechanisms of how the immune regulatory CAFs are activated and what factors regulates their differentiation and biology. Considerable evidence suggests the interleukin 1alpha (IL-1alpha) factor regulates the evolution of CAFs and their immune suppressive biology. In addition, evidence suggests the ELF3 transcription factor mediates the activity of IL-1alpha in CAFs. It is our hypothesis that elevated IL-1alpha made by prostate cancer cells activates stem cells that are located in the walls of blood vessels to expand/differentiate to an immune modulatory CAF that is immunosuppressive and therefore tumor-promoting. Moreover, we believe that the ELF3 transcription factor is the key mediator of the stem cell activation and differentiation to the immune modulatory CAF phenotype. The overall goal of the proposed project is to identify key mechanisms that could be exploited therapeutically. The aims of the proposal are to trace the development of CAFs using novel models to show that IL-1alpha is the key regulator of stem cells in vessel walls (Aim 1). Next, we propose to study how genetic loss (silencing) of the ELF3 factor may inhibit the development of the immune regulatory CAFs (Aim 2). Finally, using a mouse tumor model system with an intact immune system, we will show how important IL-1alpha and ELF3 are to regulating CAF development, changes in immune cells that are found in the tumor, and how these relate to the rate of tumor growth. Completion of these aims will answer key questions of our hypothesis. Applicability of the Research: It is important to understand mechanisms of how the set of non-cancer CAF cells that co-evolve with cancer cells affect the immune system involvement within the tumor. If fundamental mechanisms are identified, it may be possible to develop a type of pre-immune therapy that is directed to lower the existence of CAFs or inhibit their immune suppression biology. This would be expected to improve the effectiveness of immunotherapy. Data gained from the study may even be able to help predict what patients may respond better to existing immunotherapy for prostate cancer. The immediate outcomes will be a better understanding of the role of IL-1alpha, ELF3, and CAFs in determining the immune suppressive biology within a tumor. Longer-range studies would then be possible to try to identify how to target these mechanisms therapeutically. Contributions of the Research to Advancing Prostate Cancer Research: Better tools are needed to increase the effectiveness of immunotherapy for the treatment of prostate cancer. All evidence indicates that the way a patient s immune system functions within a tumor determines how effective immune therapy will be.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710605
Entities
People
- David R. Rowley
Organizations
- Baylor College of Medicine
- United States Army