Update on HER-2 as a target for cancer therapy: HER2/neu peptides as tumour vaccines for T cell recognition

During the past decade there has been renewed interest in the use of vaccine immunotherapy for the treatment of cancer. This review focuses on HER2/neu, a tumour-associated antigen that is overexpressed in 10–40% of breast cancers and other carcinomata. Several immunogenic HER2/neu peptides recognized by T lymphocytes have been identified to be included in cancer vaccines. Some of these peptides have been assessed in clinical trials of patients with breast and ovarian cancer. Although it has been possible to detect immunological responses against the peptides in the immunized patients, no clinical responses have so far been described. Immunological tolerance to self-antigens like HER2/neu may limit the functional immune responses against them. It will be of interest to determine whether immune responses against HER2/neu epitopes can be of relevance to cancer treatment

The effect of antigen dose on T cell-targeting vaccine outcome

During the past 3–4 decades, an increasing amount of evidence has pointed to the complex role of the antigen dose or T cell receptor (TCR) stimulation strength on the subsequent type, duration and “flavor” or quality of the response. Antigen dose was initially shown to impact Th1/Th2 bias, and later also shown to differentially affect development and induction of Tregs, Th17, T-follicular helper (Tfh), cells, and others. In recent years the quality of both CD4/8 T cells during infections, cancer and/or autoimmunity has turned out to be critical for subsequent disease outcome. Importantly, different vaccination strategies also lead to different types of T cell responses, and the role of the antigen dose is emerging as an important factor as well as a tool for investigators to utilize in fine-tuning vaccine efficacy. This commentary will highlight essential background of how antigen dose can impact and affect the quality of T cell responses, and discuss how this translates in different vaccine settings

Convergence and amplification of toll-like receptor (TLR) and receptor for advanced glycation end products (RAGE) signaling pathways via high mobility group B1 (HMGB1)

Sustained proinflammatory responses in rheumatoid arthritis, atherosclerosis, and diabetic retinopathy, as well as in cancer, are often associated with increased angiogenesis that contributes to tissue disruption and disease progression. High mobility group B1 (HMGB1) has been recognized as a proinflammatory cytokine and more recently, as a proangiogenic factor. HMGB1 can either be passively released from necrotic cells or actively secreted in response to angiogenic and inflammatory signals. HMGB1 itself may signal through the receptor for advanced glycation end products (RAGE), and via toll-like receptors, TLR2 and TLR4. Activation of these receptors results in the activation of NFkappaB, which induces the upregulation of leukocyte adhesion molecules and the production of proinflammatory cytokines and angiogenic factors in both hematopoietic and endothelial cells, thereby promoting inflammation. Interestingly, HMGB1 seems to be involved in a positive feedback mechanism, that may help to sustain inflammation and angiogenesis in several pathological conditions, thereby contributing to disease progression. Endothelial cells express HMGB1, as well as the receptors RAGE, TLR2, and TLR4, and in diverse pathologies HMGB1 and its receptors are overexpressed. Furthermore, HMGB1-induced signaling can activate NFkappaB, which can subsequently induce the expression of HMGB1 receptors. Thus, HMGB1 can mediate amplification of inflammation and angiogenesis through increased secretion of HMGB1 and increased expression of the receptors it can interact with. In this review, we discuss signaling cascades that HMGB1 can induce via TLRs and RAGE, as well as its contribution to pathologies involving endothelial cells

Characterization of tumor-directed cellular immune responses in humans

Understanding tumor/host immune interactions may help to fight cancer. Growing knowledge about T cell responses and increasing success of immunotherapeutic approaches have created the need for methods to characterize tumor-directed cellular immune responses. The spectrum of methods reaches from protein-based methods, including tetramers or intracellular flow cytometry, to genetic assays, such as TCR analysis or microarray techniques, further on to functional assays analysing proliferation and microtoxicity. Here, we describe these and further methods and explain their respective application in human tumor immunology

CD8+ T cell efficacy in vaccination and disease

Much effort has been devoted to the design of vaccines that induce adaptive cellular immunity, in particular CD8+ T cells, which have a central role in the host response to viral infections and cancers. To date, however, the development of effective T cell vaccines remains elusive. This is due, in part, to the lack of clearly defined correlates of protection and the inherent difficulties that hinder full characterization of the determinants of successful T cell immunity in humans. Recent data from the disparate fields of infectious disease and tumor immunology have converged, with an emphasis on the functional attributes of individual antigen-specific T cell clonotypes, to provide a better understanding of CD8+ T cell efficacy. This new knowledge paves the way to the design of more effective T cell vaccines and highlights the importance of comprehensive immunomonitoring