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Research Grants Awarded
Evaluation of immune response to HERV antigens as vaccines for breast cancer
Background: Tumor-associated antigens (TAAs) recognized by the immune system are a very attractive target for human cancer therapy. However, few immunotherapy approaches have been used for the treatment of breast cancer (BC), in part because of the relatively small number of BC TAAs that have been identified. A major issue limiting the efficacy of T-cell responses is the self-nature of most targeted antigens in BC. One group of viruses that has emerged recently to be associated with cancer is human endogenous retroviruses (HERVs). Recently, we demonstrated that HERV-K env proteins are expressed in patients with BC. Objective/Hypothesis: To date, no investigations have been conducted to assess whether these HERV env proteins are TAAs in BC. Likewise, no studies have reported that these proteins are able to induce immune responses in BC patients and make them potentially useful in BC vaccines. Our hypothesis is that HERV-K env proteins expressed in BC, and immunogenic in BC patients, and may be used as TAAs for detection, diagnosis, and immunotherapy of BC. Specific Aims: 1: Determine the expression profiles of various HERV proteins in BC tissues, and correlate expression with tumor stage and grade, and patient prognosis. 2: Identify and characterize anti-HERV-specific antibody subtypes in BC patients and determine their relevance to disease stage and grade, and patient prognosis. 3: Identify HERV-K HLA class I (HLA-A*0201) and class II (HLA-DP4) epitopes stimulating CD8+ and CD4+ T-cell responses in normal donors and BC patients and their sensitivity to CD4+, CD25+ T-regulatory cell suppression. Study Design: Primary breast tissues and blood samples will be collected by our clinical team and monitored for two years after the primary surgery. One goal of this study is to assess whether activation of HERVs correlates with clinical or histological characteristics of each BC patient, and with prognostic factors associated with the patients that we propose to study. These studies will tell us whether or not the expression of HERV proteins is tumor-specific for BC. Anti-CD8+, and anti-CD4+ antibodies will be used to determine the infiltration of CD4+ and CD8+T cells. A second goal is to determine if circulating antibodies to HERV-K env protein and other HERV proteins can be detected in patients with BC. We will correlate anti-HERV antibody responses with CD3, CD4, and CD8 infiltration, in order to identify interactions important in the immune control of BC. Finally, we will determine whether HERV env proteins can be used as TAAs against BC by analyzing BC patient and normal donor T-cell responses against HERV-K and identifying specific HLA class I and HLA class II epitopes activating CD8+ and CD4+ T cells. Potential Outcomes: The successful implementation of the proposed study would provide useful information on the potential of HERV env proteins as TAAs for detection, diagnosis, and immunotherapy regimens against BC.
Breast cancer (BC) is the most common cancer in women. Our recent studies have suggested that many human tumors may express normally silent HERV genes, leading to the suggestion that HERV may be involved in the pathogenesis of disease. The most promising findings of our studies to date are that HERV-K env proteins are expressed in BC tissues, but not in normal breast tissues. The presence of serum antibodies suggests that HERV proteins may be immunogenic and therefore capable of acting as tumor-associated antigens (TAAs). The question we will address in this grant proposal is whether these breast tumor specific proteins can be used to develop a vaccine against BC. We hypothesize that these HERV env proteins may interfere with host immune response. In this study, we will build on our preliminary findings, and explore the potential application of HERVs as immunotherapeutic vaccine antigens. Our goals are: 1. To obtain the expression profiles of HERV proteins in human normal breast and BC tissues. The goal of this section of Aim 1 is to assess whether activation of HERVs correlates with clinical or histological characteristics of each BC patient, and with prognostic factors associated with the patients that we propose to study. 2. To determine if circulating antibodies against various HERV env proteins can be detected in patients with BC and if the antibody titer can be correlated with clinical parameters, such as disease stage and relapse. We will correlate anti-HERV antibody responses with CD4 and CD8 infiltration, in order to identify interactions important in the immune control of BC. 3. The focus of this Aim is characterization of HERV derived proteins as novel TAAs to induce cellular immune responses against BC in vitro. CTL immune response can be elicited by HERV env protein-pulsed DCs from blood cells obtained from patients with BC. T cell reactivity will be analyzed in the PBMC and IVS cells. We intend to demonstrate that T cell immunity to HERV derived antigens is present in patients. We will use HERV antigen to enhance immune response. Furthermore, we will employ anti-CTLA-4 antibody to break immune tolerance in BC patients to prevent clonal deletion or Treg modulation. We predict that a combination of enhanced immune response and breaking of immune tolerance will optimize BC immunotherapy. We have assembled a team with 1) experience in HERV expression in cancer, 2) expertise in BC for procurement and assessment of patient samples, and 3) expertise in tumor immunology, to accomplish the Aims of the proposal. Successful completion of this proposal will provide a new strategy for treatment of BC.