TH1 and TH2 are two helper T-cell subpopulations that control the nature of an immune response by secreting a characteristic and mutually antagonistic set of cytokines: Clones of TH1 produce IL-2 and IFN-γ, whereas TH2 clones produce IL-4, IL-5, and IL-10 (86). A similar dichotomy between TH1-and TH2-type responses was reported in humans (87,88). Human IL-10 inhibits the production of IFN-γ and other cytokines by human peripheral blood mononuclear cells and by suppressing the release of cytokines (IL-1, IL-6, IL-8, and TNF-α) by activated monocytes (89–92). IL-10 down-regulates class II MHC expression on monocytes, resulting in a strong reduction in the antigen-presenting capacity of these cells (92). Together, these observations support the concept that IL-10 has an important role as an immune-inhibitory cytokine. Additional T-cell subsets were identified, including Th17 cells and regulatory T cells (Treg). Th17 cells are a distinct, pro-inﬂammatory T-cell subset, which is functionally characterized by mediating protection against extracellular bacteria and by its pathogenic role in autoimmune disorders (93–98). Th17 cells characteristically produce IL-17, CXCL13 (a B-cell stimulatory chemokine), IL-6, and TNF-α, in contrast to Th2 cells, which characteristically produce IL-4, IL-5, IL-9 and IL-13, or Th1 cells, which produce IFN-γ (Fig. 6.2). Treg cells constitute another subset of CD4-positive T cells that participates in the maintenance of immunologic self-tolerance by actively suppressing the activation and expansion of self-reactive lymphocytes. Treg cells are characterized by the expression of CD25 (the IL-2 receptor chain) and the transcription factor FoxP3 (99,100). Treg cell activity is thought to be important in preventing the development of autoimmune diseases. Removal of Treg may enhance immune responses against infectious agents or cancer. Although much remains to be learned about the role of Treg activity in antitumor immunity, it is clear that such cells may play a role in modulating host responses to cancer.
Because epithelial cancers of the ovary usually remain confined to the peritoneal cavity, even in the advanced stages of the disease, it was suggested that the growth of ovarian cancer intraperitoneally could be related to a local deficiency of antitumor immune effector mechanisms (102,103). Studies showed that ascitic ﬂuid from patients with ovarian cancer contained increased concentrations of IL-10 (102). Various other cytokines are seen in ascitic ﬂuid obtained from women with ovarian cancer, including IL-6, IL-10, TNF-α, granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF) (103). A similar pattern was seen in serum samples from women with ovarian cancer with elevations of IL-6 and IL-10.
TNF-α is a cytokine that can be directly cytotoxic for tumor cells, can increase immune cell–mediated cellular cytotoxicity, and can activate macrophages and induce secretion of monokines. Other biologic activities of TNF-α include the induction of cachexia, inﬂammation, and fever; it is an important mediator of endotoxic shock.
Cytokines are extraordinarily pleiotropic with a bewildering array of biologic activities, including some outside the immune system (55,56,77,83). Because some cytokines have direct or indirect antitumor and immune-enhancing effects, several of these factors are used in the experimental treatment of cancer.