CD4+ T cells are able to promote tumor growth through inhibition of tumor-specific CD8+ T-cell responses in tumor-bearing hosts

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.