Systemic CTLA-4 blockade ameliorates glioma-induced changes to the CD4 ⁺ T cell compartment without affecting regulatory T-cell function

Purpose: Patients with malignant glioma suffer global compromise of their cellular immunity, characterized by dramatic reductions in CD4⁺ T cell numbers and function. We have previously shown that increased regulatory Tcell (T_reg) fractions in these patients explain T-cell functional deficits. Our murine glioma model recapitulates these findings. Here, we investigate the effects of systemic CTLA-4 blockade in this model. Experimental Design: A monoclonal antibody (9H10) to CTLA-4 was employed against well-established glioma. Survival and risks for experimental allergic encephalomyelitis were assessed, as were CD4⁺ T cell numbers and function in the peripheral blood, spleen, and cervical lymph nodes. The specific capacities for anti-CTLA-4 to modify the functions of regulatory versus CD4⁺CD25^- responder T cells were evaluated. Results: CTLA-4 blockade confers long-term survival in 80% of treated mice, without eliciting experimental allergic encephalomyelitis. Changes to the CD4 compartment were reversed, as anti-CTLA-4 reestablishes normal CD4 counts and abrogates increases in CD4⁺CD25⁺Foxp3⁺GITR ⁺ regulatory T cell fraction observed in tumor-bearing mice. CD4 ⁺ T-cell proliferative capacity is restored and the cervical lymph node antitumor response is enhanced. Treatment benefits are bestowed exclusively on the CD4⁺CD25^- T cell population and not T _regs, as CD4⁺CD25^- T cells from treated mice show improved proliferative responses and resistance to T_reg-mediated suppression, whereas T_regs from the same mice remain anergic and exhibit no restriction of their suppressive capacity. Conclusions: CTLA-4 blockade is a rational means of reversing glioma-induced changes to the CD4 compartment and enhancing antitumor immunity. These benefits were attained through the conferment of resistance to T_reg-mediated suppression, and not through direct effects on T_regs.