The critical role of Th1-dominant immunity in tumor immunology

Abstract

To investigate the precise role of antigen-specific Th1 and Th2 cells in tumor immunity, we developed a novel adoptive tumor-immunotherapy model using OVA-specific Th1 and Th2 cells and an OVA gene-transfected tumor. This therapeutic model demonstrated that both antigen-specific Th1 and Th2 cells had strong antitumor activity in vivo with distinct mechanisms. However, immunological memory suitable for the generation of tumor-specific cytotoxic T lymphocytes was induced only when tumor-bearing mice received Th1 cell therapy, but not Th2 cell therapy. Thus it was strongly suggested that Th1-dominant immunity is critically important for the induction of antitumor cellular immunity in vivo. We also proposed that several immunomodulating protocols using interleukin (IL)-12, IL-12 gene, the natural killer T cell ligand alpha-galactosylceramide, or Th1 cytokine-conditioned dendritic cells might be useful strategies for the induction of Th1-dominant immunity essential for the development of tumor-specific immunotherapy.

Natural killer T cell activation overcomes immunosuppression to enhance clearance of postsurgical breast cancer metastasis in mice

“…1B, C). Consistent with an important role for IFNg in tumor control, 33,34 there were significant reductions in lung metastasis one week (Day 21) following treatment with a-GalCer or a-C-GalCer, but not with OCH (Fig. 1D).…”

Harnessing the immune response to treat cancer

“…This is again dependent on IL-2 secretion , consistent with the finding that mice cured of tumour through the adoptive transfer of Th1 cells acquired immunological memory, whereas those cured by transfer of Th2 cells did not (Nishimura et al, 2000). In contrast, those CD8 cells that do not receive CD4 help during priming die following secondary contact with antigen, partly mediated by upregulation of the TRAIL receptor DR5 (Janssen et al, 2005).…”

IL-12p70 and IL-18 gene-modified dendritic cells loaded with tumor antigen-derived peptides or recombinant protein effectively stimulate specific Type-1 CD4+ T-cell responses from normal donors and melanoma patients in vitro

“…1,2 While most vaccine studies have focused solely on effector CD8 þ T-cell responses as surrogates for clinical cancer responses, it is now clear that antitumor CD4 þ T cells regulate the quality, magnitude and durability of CD8 þ cytotoxic T lymphocyte (CTL) immunity in vivo, [3][4][5] and that the Type-1T helper (Th1) cytokine, interferon-g (IFN-g), plays an essential role in this response. Th1-type CD4 þ T cells secrete IFN-g and may mediate delayed-type hypersensitivity responses that can lead to enhanced cross-presentation of tumor antigens by host antigen-presenting cells (APCs), 6 and consequent epitope spreading in the evolving antitumor T-cell repertoire.…”

“…Th1-type CD4 þ T cells secrete IFN-g and may mediate delayed-type hypersensitivity responses that can lead to enhanced cross-presentation of tumor antigens by host antigen-presenting cells (APCs), 6 and consequent epitope spreading in the evolving antitumor T-cell repertoire. 7,8 Furthermore, CD4 þ T cells may mediate direct tumoricidal activity via tumor necrosis factor (TNF) family ligand members and can inhibit tumor angiogenesis via locoregional production of IFN-g. [9][10][11][12] Antitumor Th1-type CD4 þ T cells, however, appear inhibited in many cancer patients, 5,13,14 as reflected by decreased proliferation and T-cell receptor signaling, 15 as well as by increased frequencies and activity of regulatory T cells. 16,17 Whereas Th1-type responses have been associated with spontaneous or therapy-induced regression of tumor lesions, 14,18 tumor-infiltrating lymphocytes isolated from patients with progressive lesions have been generally reported to exhibit dominant Th2-type (secreting interleukin (IL)-4, IL-5) or regulatory (Th3)-type (secreting IL-10, TGF-b1) responses.…”