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Molecular Immunological Approaches to Biotherapy of Human Cancers – a Review, Hypothesis and Implications*

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Molecular Immunological Approaches to Biotherapy of Human Cancers – a Review, Hypothesis and Implications* ANTICANCER RESEARCH 26: 1113-1134 (2006) Review Molecular Immunological Approaches to Biotherapy of Human Cancers – A Review, Hypothesis and Implications* YECHIEL BECKER Department of Molecular Virology, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel Abstract. The immune system of the human organism with Th2 cytokine antagonists. This new approach to cancer comprises the innate system cells and the adaptive immune treatment will be supplemented by co-treatment with CpG cells. The former include the hematopoietic cells, mast cells, oligodeoxynucleotides(ODNs) which reactivate the adaptive basophils, monocytes, dendritic cells (DCs) and macrophages, antitumor immune respnse. Studies that provide information and the latter include CD4+ T cells, CD8+ T cells, T on the efficiency of CpG ODN treatment of tumors in mice regulatory cells (Tr) and B cells. The innate system DCs are revealed that tumor regression was achieved by inducing Toll- + + the major antigen-presenting cells to Tho CD4 T cells in like receptor 9 plasmacytoid dendritic cells (PDCs) to release lymph nodes that polarize into T helper 1 (Th1) and T helper 2 large amounts of type I interferons (IFN alpha and beta), (Th2) cells, which subsequently produce different cytokines. which inhibit Th2 cytokine synthesis by hematopoietic cells and Polarized Th1 cells produce interleukin (IL)-2, IL-12 and CD4+ T cells and enhance Th1 cytokine synthesis and interferon (IFN)-gamma, and polarized Th2 cells and the activation of the adaptive immunity. It is hypothesized that hematopoietic cells produce IL-4, IL-5, IL-6, IL-10 and IL-13. Th2 cytokine (IL-4 and IL-6) antagonists may be an effective In healthy individuals there is a Th1/Th2 cytokine balance, but treatment for cancer patients since cytokine antagonists inhibit during microbial-induced inflammation the pathogens induce the increased Th2 cytokines in patients. Such an approach may an overproduction of the Th2 cytokines that inhibit the replace Th2 cytokine monoclonal antibodies, the current adaptive immune response against the pathogen. A review of treatment for cancer patients. It is hypothesized that the studies on the Th1/Th2 cytokine balance in humans harboring effective treatment of cancer patients with Th2 cytokine different tumor types revealed that tumor cells induce increased antagonists, combined with CpG ODNs, will lead to the Th2 cytokine levels in patients’ sera that can serve as indicators inhibition of Th2 cytokines and reactivation of the Th1- for the existence of tumors. In this review, studies which induced antitumor adaptive immunity that will destroy tumor correlated the presence of increased Th2 cytokines with the cells and cure cancer patients. presence of early tumors and tumor progression are discussed. It was suggested that early monitoring of human populations A. Introduction and Aims for elevated Th2 cytokines may be used to identify individuals at an early stage of tumor development. A hypothesis is a. The relationship between the innate and adaptive presented which suggests that increased Th2 cytokine synthesis immune systems in healthy individuals and cancer in cancer patients, with early and late tumors, may be treated patients Human cancers, as well as plant remedies to treat cancer patients, have been known since 2000 BC. At the beginning *Presented at the symposium on "Multidrug and Drug Resistance", of the 20th century, Paul Ehrlich studied the chemical a special symposium supported by Action Cost B16 "Reversal of effects of paramidobensol, phenylarsenoxyl, diamido- Antibiotic Resistance" at the Seventh International Conference of arsenobenzol and pyocyanase on carcinomas and sarcoma Anticancer Research, October 25-30, 2004, Corfu, Greece. (1). These studies initiated the concept that chemicals can be used to cure microbial infections and human tumors. Correspondence to: Yechiel Becker, Department of Molecular With the discovery of the structure of DNA by Watson and Virology, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel. e-mail: [email protected] Crick and the subsequent development of molecular biology during the second part of the 20th century, research on Key Words: Biotherapy, immunotherapy, review. mutations in cellular DNA genomes caused by exposure to 0250-7005/2006 $2.00+.40 1113 ANTICANCER RESEARCH 26: 1113-1134 (2006) toxic chemicals and UV or X-rays have led to the collaborate to stop the mutated tumor cells from developing understanding of the role of human genes in tumor cell into metastatic cancer cells. Therefore, understanding the cycle regulation. These studies allowed rational analysis of mechanisms by which tumor cells evade the host immune the sequence of events that leads to tumor development (2). systems is the subject of the present review. Current studies Hanahan and Weinberg (2) indicated that: "tumorigenesis on the response of immune system cells to tumors and to in humans is a multistep process and these steps reflect their antigens and the response of tumor cells to the host alterations that drive the progressive transformation of cytokines and chemokines provide the basis for our normal human cells into highly malignant derivatives". The hypothesis that the gradual development of a tumor into a authors suggested that: "the vast catalog of cancer cell metastatic entity depends on the tumor’s ability to inhibit genotypes is the manifestation of six essential alterations in the development of the adaptive immune response by cell physiology that collectively dictate malignant growth: antitumor cytotoxic T cells (CTLs) and synthesis of self-sufficiency in growth signals, insensitivity to growth- antitumor antibodies. Tumors are able to enhance the inhibitors (antigrowth) signals, evasion of programmed cell synthesis of T helper 2 (Th2) cytokines interleukin (IL)-4 death (apoptosis), limitless replicative potential, sustained and IL-10 by hematopoietic cells, members of the innate angiogenesis, and tissue invasion and metastasis" (2). The immune system. Based on published reports, it is possible authors concentrated on the intracellular molecular events that, by treating cancer patients with specific cytokine that transform normal cells into metastatic cancer cells, but antagonists and CpG oligodeoxynucleotides (ODNs), did not deal with the impact of tumors on the host cytokine inducers of plasmacytoid dendritic cells (PDCs) to release and chemokine networks and the inflammatory processes in large amounts of type I interferons, the adaptive immune the tissue microenvironment of developing tumors. response of the cancer patients will be reactivated to clear Parallel to developments in the understanding of the drug-resistant and -sensitive tumors and inhibit tumor molecular mechanisms governing the gradual alterations in growth and progression. normal cells in vivo that lead to malignancy, molecular targets for chemotherapy have been defined, leading to the b. The human innate and adaptive immune system development of targeted cancer chemotherapy. However, cells and the Th1/Th2 cytokines prolonged chemotherapy which caused tumor remission also caused tumor cells to become resistant to anticancer drugs. The human immune systems are divided into the innate Tumor remission is replaced by the re-emergence of drug- (ancient) cell system and the adaptive immune system. The resistant tumors. Longley and Johnston (3) indicated that: innate system cells provide the cytokines which activate the "acquired resistance by tumors is a particular problem, as adaptive immune system cells. tumors not only become resistant to the drugs originally 1) The innate immune system cells. Figure 1A presents the used to treat them, but may also become cross-resistant to bone marrow-derived cell types that constitute the human other drugs with different mechanisms of action. Resistance innate immune system: to chemotherapy is believed to cause treatment failure in (a) The monocytes are able to differentiate into over 90% of patients with metastatic tumors." The macrophages (5), scavengers of dead cell debris and mechanisms of chemotherapeutic drug influx into tumor invading microorganisms, and DCs (4), the professional cells are not known, but drug-resistant tumors induce antigen-presenting cells. DCs present in the skin epithelium expression of the ABC transporter proteins (e.g., (Langerhans cells (LCs) (6)) and in all body tissues are the P-glycoprotein (PgP) and multidrug resistance protein sentinels that capture cancer cell debris and invading (MRP) cause drug efflux that cyclosporine inhibits, with pathogens. DCs and LCs use lectin-like DC-SIGN receptors toxic effects, while the PgP inhibitors tariquidar and to bind tumor cell debris and microorganisms for zosuquidar are being tested in phase III clinical trials (3)). engulfment into the cytoplasm and degradation by the Chemotherapeutic drugs and ionizing radiation are the proteasomes. The cancer cell antigens are presented by the current treatments to stop the development of human DC HLA class I and class II molecules to naïve T cells upon tumors. Chemotherapy has led to tumor remission, but the arrival of the DCs/LCs in the draining lymph nodes. The development of drug-resistant relapsing tumors remains an PDCs (7) express Toll-like receptor 9 that binds bacterial unresolved problem. unmethylated DNA, and release type I interferons (IFN)- During the last twenty years, research on the biology and alpha and -beta. Monocytes and DCs release Th2 cytokines molecular aspects
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