Synergism of Cytotoxic T Lymphocyte–Associated Antigen 4 Blockade and Depletion of Cd25+ Regulatory T Cells in Antitumor Therapy Reveals Alternative Pathways for Suppression of Autoreactive…

By R. Sutmuller, L. V. van Duivenvoorde, A. van Elsas, Ton N. Schumacher, M. Wildenberg, James P. Allison, R. Toes, R. Offringa, C. Melief. Journal of Experimental Medicine, 2001

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Therapeutic efficacy of a tumor cell–based vaccine against experimental B16 melanoma requires the disruption of either of two immunoregulatory mechanisms that control autoreactive T cell responses: the cytotoxic T lymphocyte–associated antigen (CTLA)-4 pathway or the CD25+ regulatory T (Treg) cells. Combination of CTLA-4 blockade and depletion of CD25+ Treg cells results in maximal tumor rejection. Efficacy of the antitumor therapy correlates with the extent of autoimmune skin depigmentation as well as with the frequency of tyrosinase-related protein 2180–188–specific CTLs detected in the periphery. Furthermore, tumor rejection is dependent on the CD8+ T cell subset. Our data demonstrate that the CTL response against melanoma antigens is an important component of the therapeutic antitumor response and that the reactivity of these CTLs can be augmented through interference with immunoregulatory mechanisms. The synergism in the effects of CTLA-4 blockade and depletion of CD25+ Treg cells indicates that CD25+ Treg cells and CTLA-4 signaling represent two alternative pathways for suppression of autoreactive T cell immunity. Simultaneous intervention with both regulatory mechanisms is therefore a promising concept for the induction of therapeutic antitumor immunity.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/4dc893dc31d0bac786a59d3bb35b094d4fef4dc7

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Citations in the corpus

Prevalence of Regulatory T Cells Is Increased in Peripheral Blood and Tumor Microenvironment of Patients with Pancreas or Breast Adenocarcinoma1 (2002, background): “When Treg are depleted using mAb, transplanted tumors in mice are efficiently rejected by the host immune system (11, 12).”
Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti–CTLA-4 therapy against melanoma (2013, background): “…was that anti–CTLA-4 antibodies (–CTLA-4) function by blocking inhibitory signals into effector T cells (T eff cell; Krummel and Allison, 1996; Sutmuller et al., 2001), the demonstration that CD4+Foxp3+ regulatory T cells (T reg cell) express high levels of CTLA-4 led to the suggestion that…”
Cancer immunotherapy (2012, background): “Multi-center phase II trials with this agent in melanoma are ongoing with careful correlative assays being integrated. mAbs against CD25 also have begun to be explored in the clinic, mimicking themost effective strategy that has been used in mouse models (Sutmuller et al., 2001).”
Cutting Edge: Regulatory T Cells from Lung Cancer Patients Directly Inhibit Autologous T Cell Proliferation1 (2002, background): “A recent study in mice suggests that the efficacy of therapeutic cancer vaccination in mice can be enhanced by removing CD4 CD25 T cells (22).”