In Vivo RNAi Screens to Identify Novel T Cell-Dependent Immunotherapeutic Targets of Breast Cancer
Abstract
There has been a remarkable breakthrough in cancer therapy in the last few years from antibody therapies that activate the immune system to kill cancer cells, leading to highly effective and durable treatments for such aggressive cancers as late-stage melanoma. However, there are only a few known proteins, called checkpoint inhibitors, which block tumor killing from immune cells called cytotoxic T cells, and therapies targeting these proteins only work on subsets of patients for certain cancers. We present here a unique discovery platform to identify new immunotherapy targets, using a viral gene disruption technology, called RNAi, a DNA-like molecule. Each gene in our genome is made up of DNA and provides the instructions for the cell to make one specific protein. RNAi acts as a mimic of the DNA in one specific gene and prevents the cell from making the corresponding protein, which we can deliver to cells with a virus. Since almost all drugs work by blocking a specific protein from doing its normal job in the cell, we can identify which proteins are important for cancers to grow by knocking them down one at a time, and thus finding which ones make good targets for drugs. Looking at the effects of many of these viral RNAis in parallel, called an RNAi screen, can be done on cancer cells in isolation on plastic dishes, but when done in a mouse, in vivo, provide results that are much more likely to translate to human medicine and allows study of the immune response to cancer. The Principal Investigator (PI) on this proposal, Dr. Pipkin, is part of one of a handful of labs worldwide to have published an in vivo RNAi screen, and one of only two labs to have done so in immune cells. The Co-PI, Dr. Nettles, is an expert on drug discovery targeting inflammatory signaling in ER+ breast cancer and is now building the breast cancer model systems to implement Dr. Pipkin s screens and identify the next generation of immunotherapies. Background on immunotherapies and our approach: We have specialized immune cells that travel through the blood to find and destroy foreign life, whether bacteria, virus, or our own tissues that have become modified from normal cells, such as cancer. Many of these immune cells have specialized types of proteins called antibodies that act to stick to and recognize other proteins. They can be secreted from cells and circulate in the blood to stick to things and tag them for killing or reside on the surface of immune cells such as T cells where they are called T-cell receptors (abbreviated as TCR). Antibodies make very effective drugs because they tend to be very specific, only binding to the one protein they are designed to recognize. T cells are a type of immune cell that are developed in the body where each T cell has a unique TCR designed to recognize a different protein. The T cells are then exposed to normal proteins during development and killed, leaving only T cells that have TCRs to recognize foreign proteins. Almost all cells have the ability to chew up proteins and present them on their surfaces, allowing the T cells to "taste" them to see if the proteins are normal or foreign, and if a specific T-cell recognizes the one foreign protein it is made to recognize, it starts rapidly dividing and starts generating toxic materials, called granules, that are expelled and that kill the cells with the foreign protein. Importantly, tumors can make proteins on their surface that recognize the checkpoint inhibitor proteins on the T cell. This causes the T cells to become less active in tumor killing, and they may then kill only a subset of the cells, leading to outgrowth of resistant cells. This is called immunoediting. We hypothesize that there are other, undiscovered such proteins on breast tumors, in addition to the few that are known, which can be targeted to provide curative, non-toxic therapies for breast cancer patients. Our goal is to identify cell surface proteins on breast cancer ce
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1610006
Entities
People
- Matthew Pipkin
Organizations
- Scripps Research
- United States Army