Tumor antigen-specific T helper cells in cancer immunity and immunotherapy

Abstract

Historically, cancer-directed immune-based therapies have focused on eliciting a cytotoxic T cell (CTL) response, primarily due to the fact that CTL can directly kill tumors. In addition, many putative tumor antigens are intracellular proteins, and CTL respond to peptides presented in the context of MHC class I which are most often derived from intracellular proteins. Recently, increasing importance is being given to the stimulation of a CD4+ T helper cell (Th) response in cancer immunotherapy. Th cells are central to the development of an immune response by activating antigen-specific effector cells and recruiting cells of the innate immune system such as macrophages and mast cells. Two predominant Th cell subtypes exist, Th1 and Th2. Th1 cells, characterized by secretion of IFN-gamma and TNF-alpha, are primarily responsible for activating and regulating the development and persistence of CTL. In addition, Th1 cells activate antigen-presenting cells (APC) and induce limited production of the type of antibodies that can enhance the uptake of infected cells or tumor cells into APC. Th2 cells favor a predominantly humoral response. Particularly important during Th differentiation is the cytokine environment at the site of antigen deposition or in the local lymph node. Th1 commitment relies on the local production of IL-12, and Th2 development is promoted by IL-4 in the absence of IL-12. Specifically modulating the Th1 cell response against a tumor antigen may lead to effective immune-based therapies. Th1 cells are already widely implicated in the tissue-specific destruction that occurs during the pathogenesis of autoimmune diseases, such as diabetes mellitus and multiple sclerosis. Th1 cells directly kill tumor cells via release of cytokines that activate death receptors on the tumor cell surface. We now know that cross-priming of the tumor-specific response by potent APC is a major mechanism of the developing endogenous immune response; therefore, even intracellular proteins can be presented in the context of MHC class II. Indeed, recent studies demonstrate the importance of cross-priming in eliciting CTL. Many vaccine strategies aim to stimulate the Th response specific for a tumor antigen. Early clinical trials have shown that focus on the Th effector arm of the immune system can result in significant levels of both antigen-specific Th cells and CTL, the generation of long lasting immunity, and a Th1 phenotype resulting in the development of epitope spreading.

Delivery of antigen using a novel mannosylated dendrimer potentiates immunogenicity in vitro and in vivo

“…Immunization with a higher dose of MDO stimulates both CD4 and CD8 responses, resulting in distinctive protection from rapid development of B16-OVA melanoma. These results perhaps indicate the cooperative helper CD4 response is required for competent anti-tumor immunity in addition to the CD8 response [40]. In addition, the capacity of MDO to stimulate a distinctive level of the humoral response proposes the potential role of MDconjugated antigens in targeting infectious diseases, which can impact on the vaccine design.…”

Unmasking of α-Fetoprotein-Specific CD4+ T Cell Responses in Hepatocellular Carcinoma Patients Undergoing Embolization

“…In theory, however, an effective peptide-based tumor vaccine for HCC may be most effective if both CD8 ϩ and CD4 ϩ T cell responses against tumor-associated Ags are induced (26,27). Helper T cells play an important role in promoting CD8 ϩ T cell memory development and activating tumor-associated Ag-specific memory CTLs (28,29).…”

Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment

“…CD8+ cytotoxic T cells (CTLs) together with NKs are the fundamental effectors of immune response-mediated tumor cell elimination via the release of cytokines that activate death receptors on the tumor cell surface. CD4+ T helper cells are central to the development of immune responses by activating antigen-specific effector cells and recruiting cells of the innate immune system [242,243]. As mentioned earlier, suppressor T cells play an important role in inducing tumor immunotolerance, which might not only allow tumor growth but also metastasis [237,244].…”