Prostate Cancer Antigen Presentation by HLA-E as a New Target Mechanism for Immunotherapy
Abstract
Major histocompatibility (MHC) molecules present protein fragments (peptides) to receptors on killer T cells. Cancer immunotherapies generally attempt to target such T cells to peptides derived from proteins that are specific to a given tumor (=tumor antigens). To improve outcomes of metastatic prostate cancer, all currently approved immunotherapies and immunotherapies in clinical testing attempt to activate T cells that recognize their target peptide when presented by “classical” MHC molecules, i.e., molecules that are highly diverse in the human population (hence the need for MHC-matching of transplants). Tumor cells usually modify or suppress expression of these classical MHC molecules as an evasion strategy to avoid becoming targets of T cells, and thus the treatment fails. There is, however, a “nonclassical” MHC molecule that has never been explored for cancer immunotherapy purposes. In this project, we will explore the idea that non-classical MHC-E molecules that are highly conserved in all humans can be targeted for immunotherapy of prostate cancer. Up to now it was not possible to explore such a concept because the scientific community did not have the tools to generate T cells that recognize peptides presented by MHC-E. However, recent progress in developing vaccines for AIDS and tuberculosis for the first time enables the induction of T cells that recognize tumor antigens presented by MHC-E. In preliminary studies, we observed that MHC-E (called HLA-E in humans) is highly upregulated in prostate tumors, whereas normal prostate or adjacent, normal tissue had low levels of MHC-E. Furthermore, we were able to show that prostate acid phosphatase (PAP)-specific, MHC-E-targeting T cells recognize a prostate cancer cell line, a finding that strongly suggests that prostate cancer cells have the capability to generate and load peptides onto MHC-E. In order to develop MHC-E-targeting treatments for prostate cancer, we first need to develop a better understanding of whether the same peptides are presented by MHC-E on prostate cancer cells obtained from different patients and how T cells recognize these peptides. Studies proposed here will close this knowledge gap. Upon completion of these studies, we anticipate that we will be able to develop and clinically test immunotherapies that specifically target prostate cancer antigens presented by MHC-E. Such immunotherapies could either be based on vaccines that elicit such T cells upon inoculation into humans or on using the patients’ T cells that have been modified to carry receptors specific for MHC-E/peptide complexes. Either of these immunotherapy approaches would be fundamentally different from currently available treatments and, as such, might be a game changer in our ability to treat prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910358
Entities
People
- Klaus Frueh
Organizations
- Oregon Health & Science University
- United States Army