A Functional Genomics Approach to Identify Renal Cell Carcinoma Antigens Targeted by T Cells in the Tumor Microenvironment
Abstract
One of the most exciting breakthroughs in cancer therapy in the past decade has been the realization that a type of blood cell from the immune system called T cells can be harvested from patients, engineered to specifically recognize tumor cells, grown to large numbers, and returned to the patient as a living and durable army of tumor-killing cells. This approach, known as T-cell immunotherapy, has revolutionized the treatment of several types of blood cancers and there is intense interest in expanding this approach to kidney cancer. However, kidney cancer cells lack the targets, known as tumor antigens, for T-cell therapies currently in advanced clinical development for other tumors. The discovery of new antigens in kidney cancer that can serve as targets for T cells is urgently needed to facilitate the development of new T-cell immunotherapies. These targets can also lead to the development of therapeutic antitumor vaccines. We have identified T cells from patients that can recognize and kill kidney cancer cells in the laboratory. Recent advances in DNA-sequencing technology have enabled us to determine the unique genetic sequences of the proteins on these T cells, called T-cell receptors, that are responsible for recognizing specific antigens on the kidney cancer cells. These antigens are typically small fragments of proteins known as peptides that are processed and presented on the surface of tumor cells for inspection and recognition by the T cells. Identifying the array of peptide antigens that can be recognized by potentially therapeutic T cells is critical for the development of T-cell immunotherapy in kidney cancer. This step is necessary in order to select a specific T-cell receptor to equip therapeutic T cells to recognize tumor antigens and kill tumor cells while avoiding normal cells. However, conventional methods for peptide antigen identification are difficult to implement, and there is currently only a limited understanding of potential kidney cancer antigen targets for clinical development. In this project, we will for the first time apply a recently developed technology called whole genome editing as a novel platform to discover kidney cancer antigens recognized by T cells. In this approach, millions of kidney cancer cells are treated with a pool or library of DNA-recognizing enzymes that function as molecular scissors. This approach removes one and only one gene at a time in each cell, representing, in total, all 19,050 protein-coding genes in the human genome. After growing the pool of these kidney cancer cells together with T cells that are known to kill the tumor cells, the only cells that survive are those in which the inactivated genes are those responsible for antigen generation, processing, or presentation on the cell surface. Using a next-generation DNA-sequencing approach called massively parallel sequencing, the specific genes that were removed in the surviving cells can be deduced. In this way, for each T cell in our panel of kidney cancer reactive T cells that can kill the tumor cells, we will identify the gene in the tumor cells responsible for encoding the protein that is used to generate the peptide antigen. The research in this Idea Development Award project addresses the critical Fiscal Year 2020 KCRP Area of Emphasis to understand the basic and translational science of the tumor microenvironment and immunology in kidney cancer. If successful, this project will identify new kidney cancer antigen targets. This project will set the stage for first-in-human clinical trials of T-cell immunotherapy and therapeutic vaccines within the next 3 years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110809
Entities
People
- Edus H Warren
Organizations
- Fred Hutchinson Cancer Center
- United States Army