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Systemic CTLA-4 Blockade Ameliorates Glioma-Induced Changes to the CD4⁺ T Cell Compartment without Affecting Regulatory T-Cell Function

Authors' Affiliations: Division of Neurosurgery, Departments of ¹ Surgery and ² Pathology, Duke University Medical Center, Durham, North Carolina; ³ Department of Neurosurgery, University of Miyazaki, Kihara, Kiyotake, Miyazaki, Japan; and ⁴ Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York

Requests for reprints: John H. Sampson, Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, NC 27710. Phone: 919-684-9043; Fax: 919-684-9045; E-mail: john.sampson{at}duke.edu.

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 T cell (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.

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