Molecular immunological approaches to biotherapy of human cancers--a review, hypothesis and implications.

The immune system of the human organism comprises the innate system cells and the adaptive immune cells. The former include the hematopoietic cells, mast cells, basophils, monocytes, dendritic cells (DCs) and macrophages, and the latter include CD4+ T cells, CD8+ T cells, T regulatory cells (Tr) and B cells. The innate system DCs are the major antigen-presenting cells to Th(o) CD4+ T cells in lymph nodes that polarize into T helper 1 (Th1) and T helper 2 (Th2) cells, which subsequently produce different cytokines. Polarized Th1 cells produce interleukin (IL)-2, IL-12 and interferon (IFN)-gamma, and polarized Th2 cells and the hematopoietic cells produce IL-4, IL-5, IL-6, IL-10 and IL-13. In healthy individuals there is a Th1/Th2 cytokine balance, but during microbial-induced inflammation the pathogens induce an overproduction of the Th2 cytokines that inhibit the adaptive immune response against the pathogen. A review of studies on the Th1/Th2 cytokine balance in humans harboring different tumor types revealed that tumor cells induce increased Th2 cytokine levels in patients' sera that can serve as indicators for the existence of tumors. In this review, studies which correlated the presence of increased Th2 cytokines with the presence of early tumors and tumor progression are discussed. It was suggested that early monitoring of human populations for elevated Th2 cytokines may be used to identify individuals at an early stage of tumor development. A hypothesis is presented which suggests that increased Th2 cytokine synthesis in cancer patients, with early and late tumors, may be treated with Th2 cytokine antagonists. This new approach to cancer treatment will be supplemented by co-treatment with CpG oligodeoxynucleotides(ODNs) which reactivate the adaptive antitumor immune response. Studies that provide information on the efficiency of CpG ODN treatment of tumors in mice revealed that tumor regression was achieved by inducing Toll-like receptor 9+ plasmacytoid dendritic cells (PDCs) to release large amounts of type I interferons (IFN alpha and beta), which inhibit Th2 cytokine synthesis by hematopoietic cells and CD4+ T cells and enhance Th1 cytokine synthesis and activation of the adaptive immunity. It is hypothesized that Th2 cytokine (IL-4 and IL-6) antagonists may be an effective treatment for cancer patients since cytokine antagonists inhibit the increased Th2 cytokines in patients. Such an approach may replace Th2 cytokine monoclonal antibodies, the current treatment for cancer patients. It is hypothesized that the effective treatment of cancer patients with Th2 cytokine antagonists, combined with CpG ODNs, will lead to the inhibition of Th2 cytokines and reacTivation of the Th1-induced antitumor adaptive immunity that will destroy tumor cells and cure cancer patients.