| Abstract: |
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 (Treg) 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 Treg-mediated suppression, whereas Tregs 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 Treg-mediated suppression, and not through direct effects on Tregs. © 2007 American Association for Cancer Research. |
| Keywords: |
immunohistochemistry; cancer survival; controlled study; unclassified drug; nonhuman; flow cytometry; glioma; brain neoplasms; transcription factor foxp3; lymphocyte proliferation; animal cell; mouse; animals; mice; animal tissue; cell compartmentalization; spleen; animal experiment; animal model; cell population; monoclonal antibody; loading drug dose; cancer inhibition; cd4+ cd25+ t lymphocyte; regulatory t lymphocyte; antibodies, monoclonal; t-lymphocytes, regulatory; cd4+ t lymphocyte; cd4-positive t-lymphocytes; single drug dose; antigens, cd; cervical lymph node; cytotoxic t lymphocyte antigen 4; cd25+ t lymphocyte; glucocorticoid induced tumor necrosis factor receptor; lymphocyte count; lymphocyte function; antigens, differentiation; interleukin-2 receptor alpha subunit; allergic encephalomyelitis; encephalomyelitis, autoimmune, experimental; monoclonal antibody 9h10
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