CD4+/CD25+ Regulatory Cells Inhibit Activation of Tumor-Primed CD4+ T Cells with IFN-γ-Dependent Antiangiogenic Activity, as well as Long-Lasting Tumor Immunity Elicited by Peptide Vaccination

Abstract

CD25+ regulatory T (T reg) cells suppress the activation/proliferation of other CD4+ or CD8+ T cells in vitro. Also, down-regulation of CD25+ T reg cells enhance antitumor immune responses. In this study, we show that depletion of CD25+ T reg cells allows the host to induce both CD4+ and CD8+ antitumoral responses following tumor challenge. Simultaneous depletion of CD25+ and CD8+ cells, as well as adoptive transfer experiments, revealed that tumor-specific CD4+ T cells, which emerged in the absence of CD25+ T reg cells, were able to reject CT26 colon cancer cells, a MHC class II-negative tumor. The antitumoral effect mediated by CD4+ T cells was dependent on IFN-γ production, which exerted a potent antiangiogenic activity. The capacity of the host to mount this antitumor response is lost once the number of CD25+ T reg cells is restored over time. However, CD25+ T reg cell depletion before immunization with AH1 (a cytotoxic T cell determinant from CT26 tumor cells) permits the induction of a long-lasting antitumoral immune response, not observed if immunization is conducted in the presence of regulatory cells. A study of the effect of different levels of depletion of CD25+ T reg cells before immunization with the peptide AH1 alone, or in combination with a Th determinant, unraveled that Th cells play an important role in overcoming the suppressive effect of CD25+ T reg on the induction of long-lasting cellular immune responses.

Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: a dose escalating phase I/II study

“…This interaction may give rise to a 'second wave' of tumour reactive T cells, including CD8 þ CTLs, that are directed against unknown tumour/tissue-specific antigens (cross presentation) (Markiewicz et al, 2001). Furthermore Th cells also play an important role in overcoming the immune-suppression caused by regulatory CD4 þ CD25 þ T cells (Casares et al, 2003). The results encourage further and larger controlled clinical studies with the intermediate dose of telomerase vaccine, GV1001, in order to document the clinical benefits of the treatment indicated by this study.…”

Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy

“…In some models, transfer of Treg cells after the onset of disease can even be curative [54]. The close correlation between autoimmunity and tumor immunity [5,7,[55][56][57][58][59] suggests that Treg cells have a crucial role in T-cell tolerance to tumor [60][61][62].…”

Depletion of CD25+ cells from human T-cell enriched fraction eliminates immunodominance during priming with dendritic cells genetically modified to express a secreted protein

“…[44][45][46][47] Of interest for cancer immunotherapy is the fact that depleting these cells results in the induction of antitumor immune responses, particularly after tumor-specific vaccination. 48,49 One hypothesis is that depleting these CD4 þ CD25 þ regulatory T cells in humans enhances a polyclonal T-cell response. 21,50 Removal of CD25 þ T cells from the T-cell reactive pool prior to priming does result in elimination of immunodominance so that T cells are primed by sVac DCs to both the dominant and the subdominant epitopes (Fig 5).…”