Restored immune response to an MHC-II-restricted antigen in tumor-bearing hosts after elimination of regulatory T cells

Background/purpose Pediatric sarcomas have a poor prognosis, recur frequently, and are not effectively treated by currently available therapy. Immunotherapy is a promising treatment modality; however, to be successful, immune tolerance must be overcome. CD4⁺CD25⁺ T cells are immunosuppressive. The authors hypothesize that immune tolerance may be overcome by eliminating the regulatory CD4⁺CD25⁺ T cells, which are induced by tumor. Methods A murine fibrosarcoma (MF), which expresses an MHC-II-restricted tumor antigen (mL26), was injected subcutaneously. CD4 ⁺ T cells were isolated and CD25⁺ population examined. Monoclonal antibody was used to deplete CD25⁺ T cells. Proliferation to mL26 was used to determine CD4⁺ T cell response to tumor-associated antigen (TAA). Results Depletion of CD25⁺ cells prevented tumor establishment. Tumor-infiltrating CD25⁺ T cells, which madeup 48% of CD4⁺ T cells in tumors, suppressed proliferation in allogeneic mixed lymphocyte reactions. Draining lymph node cells from tumor-bearing (TB) mice did not proliferate in response to mL26, whereas those from naive mice responded vigorously. Depletion of CD25⁺ cells before immunization restored response to mL26 in TB mice. Conclusions CD4 ⁺CD25⁺ T cells induced by MF facilitate tumor establishment and maintain immune tolerance. Depletion of CD4 ⁺CD25⁺ T cells may be an effective means for reversing tumor tolerance and enhancing cancer vaccines.