Identification of Self-Antigens Recognized by Autoreactive T Cells from Breast Tumors
Abstract
Our immune system is a potent ally in the fight against cancer and has become a central focus of much cancer research recently as its activation has shown tremendous potential for cancer therapy. We know the immune system is important in the body’s attempt to fight breast cancer because patients with breast tumors that have more immune cells inside them show a decreased risk of relapse and death. Conversely, patients with tumors that have higher numbers of inhibitory immune cells that shut down the immune response are at higher risk with poorer prognoses. Efforts to improve the immune response therefore have the potential to positively impact the outcome of breast cancer. Multiple approaches to stimulating the immune response to cancer have been explored including various forms of immune checkpoint blockade such as anti-CTLA4, anti-PD1, and anti-PD-L1 among others, adoptive T cell therapy, and, most recently, personalized cancer vaccines. The personalized cancer vaccines focus on so-called “neo-antigens” generated by mutations in passenger genes that occur randomly during the evolution of a tumor. Fragments of the mutated proteins are combined into a vaccine that is designed to stimulate T cells to attack the tumor cells that express the mutant proteins. Such vaccines so far have only been tested for melanoma but are showing impressive results in early experiments. It is likely that similar vaccines may be tried in breast cancer in the near future. Each patient’s tumors have a different set of mutations and therefore each patient would need a personalized vaccine, which is slow and expensive. A general vaccine that might function for many if not all breast cancers would be very useful and could be applied rapidly and at lower cost. Such a general vaccine would need to be directed at self-proteins that are not mutated. Tumors often uniquely express proteins that are either tissue-specific or are only used during development or in non-essential tissues like the germline reproductive tissues. Antibodies are often seen directed at such proteins in other cancers indicating that the immune system can be activated against self-proteins in cancer. However, knowledge of which self-antigens would be the most optimal targets to direct such a vaccine towards is not known. In this proposal, we will look for recognition of self-antigens among the T cells present in breast tumors. The self-antigens recognized by T cells in existing tumors would be the ideal candidates for a general breast cancer vaccine to boost immunity towards an existing tumor to complement other therapies. Currently there is no simple way to identify the targets of self-reactive T cells in breast tumors. However, we have developed a screening method called T-SCAN that allows us to identify T cells that are self-reactive, find the self-peptide they recognize, and identify the T cell receptor with which they recognize the self-peptides. This method has been used successfully to identify the targets of antiviral T cells. In this way, we will identify the proteins to which tolerance is broken during tumorigenesis and whether they are generally shared among different breast tumors and tumor subclasses. This will be a starting point for the general unbiased study of self-antigens in breast cancer. In addition to the general study of autoimmunity in breast tumors, this knowledge has the potential for practical applications that can help treat breast cancer in the following ways: (1) The self-antigens thus identified can be used in tumor vaccines for patients whose tumors express the self-antigens and who have the matched HLA genotype. (2) The TCRs identified can be used in T cell therapies to treat patients. (3) The self-antigens identified could be used to guide the generation of preventative vaccines administered to high-risk individuals. The discovery of a general set of antigens common to many breast cancers could become the basis of new t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810469
Entities
People
- Stephen Elledge
Organizations
- United States Army