Prevention of Lung Carcinogenesis by Suppressing Pathogenic CD4 T Cells
Abstract
Chronic inflammation is increasingly recognized as an important factor that contributes to the development of a wide range of malignancies, including lung cancer. We recently found that T helper 17 (Th17) cells, a type of immune cell, is critical to inflammation. Th17 cells and their signature cytokine, interleukin-17 (IL-17), have been detected in various human cancers, but their function in tumor development remained unclear. Using genetically modified mice that develop a lung adenocarcinoma whose pathophysiology resembles that of the human disease, we demonstrated that IL-17 plays a critical pathogenic role in lung cancer development. Therefore, the mutagenesis-driven early inflammatory process in tumor is critical to lung cancer progression, and understanding the mechanisms underlying these actions will substantially advance our knowledge of cancer development and potentially lead to improved treatment strategies. In the proposed project, we will delineate the developmental pathways of inflammatory Th17 cells, which promote tumorigenesis, and those of immunosuppressive regulatory T cells (Tregs), which induce the immune system to disregard tumorigenesis. We will adapt transgenic mice to express the pathogenic cytokine IL-17 or the lineage-determining factor Foxp3, which will enable us to track and isolate Th17 cells or Tregs in a mouse model of oncogene-driven spontaneous lung cancer. Th17 cells derived from the lung adenocarcinoma of this model will be subjected to RNA sequencing to identify the molecules that enable Th17 cells to potentiate tumor progression. In addition, because T cells are known to recognize self-antigens and mutated antigens in the tumor microenvironment, we will employ high-throughput sequencing technology to identify the antigens required for Th17 cell induction. Given that pathogenic T cells promote tumor development, we also propose to use a mouse model of lung adenocarcinoma to test specific T-cell inhibitors that have been investigated in clinical trials of other malignancies or autoimmune diseases. The therapeutic agents we propose to test are an immune check point blockage anti-programmed cell death 1 antibody (for immune checkpoint blockage), and an anti-IL-17 antibody (for cytokine blockage), and phosphoinositide 3 kinase delta inhibitor (for targeting activation pathway of T cells). We hypothesize that these treatments will inhibit Th17 cells and Tregs, thereby suppressing inflammation and restoring the immune system s ability to prevent tumor growth. Upon completion of the proposed work, we will have a better understanding of currently available cancer therapies that target immune cells, and we will use this new knowledge to design therapeutic agents that are tailored to inhibit tumor growth according to the status of immune response during tumor progression.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610100
Entities
People
- Seon Hee Chang
Organizations
- United States Army
- University of Texas at Austin