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CD4⁺ T Cells Are Able to Promote Tumor Growth through Inhibition of Tumor-Specific CD8⁺ T-Cell Responses in Tumor-Bearing Hosts

Departments of ¹ Immunohematology and Bloodtransfusion and ² Rheumatology, Leiden University Medical Center, Leiden, the Netherlands

Requests for reprints: René E.M. Toes, Department of Rheumatology, Leiden University Medical Center, C4-R, P.O. Box 9600, 2300 RC Leiden, the Netherlands. Phone: 317-152-63598; Fax: 317-152-66752; E-mail: r.e.m.toes{at}lumc.nl.

Modulation of the immune response by established tumors may contribute to the limited success of therapeutic vaccination for the treatment of cancer compared with vaccination in a preventive setting. We analyzed the contribution of the CD4⁺ T-cell population to the induction or suppression of tumor-specific CD8⁺ T cells in a tumor model in which eradication of tumors crucially depends on CD8⁺ T cell–mediated immunity. Vaccine-mediated induction of protective antitumor immunity in the preventive setting (i.e., before tumor challenge) was CD4⁺ T cell dependent because depletion of this T-cell subset prevented CD8⁺ T-cell induction. In contrast, depletion of CD4⁺ cells in mice bearing established E1A⁺ tumors empowered the mice to raise strong CD8⁺ T-cell immunity capable of tumor eradication without the need for tumor-specific vaccination. Spontaneous eradication of tumors, which had initially grown out, was similarly observed in MHC class II–deficient mice, supporting the notion that the tumor-bearing mice harbor a class II MHC–restricted CD4⁺ T-cell subset capable of suppressing a tumor-specific CD8⁺ T-cell immune response. The deleterious effects of the presence of CD4⁺ T cells in tumor-bearing hosts could be overcome by CD40-triggering or injection of CpG. Together these results show that CD4⁺ T cells with a suppressive activity are rapidly induced following tumor development and that their suppressive effect can be overcome by agents that activate professional antigen-presenting cells. These observations are important for the development of immune interventions aiming at treatment of cancer.

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