Ctla4 Blockade and Gm-csf Combination Immunotherapy Alters the Intratumor Balance of Effector and Regulatory T Cells.
From: Howard Hughes Medical Institute, Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
The Journal of clinical investigation
- Publish Date: Jul 2006
- ISSN: 0021-9738
- Volume: 116
- Issue: 7
- Pages: 1935-45
- Medium: Print
- Language: English
- Citation (JAMA): Quezada Sergio A, Peggs Karl S, Curran Michael A, et al. Ctla4 Blockade and Gm-csf Combination Immunotherapy Alters the Intratumor Balance of Effector and Regulatory T Cells.. J. Clin. Invest. Jul 2006;116:1935-45
Abstract
CTL-associated antigen 4 (CTLA4) blockade releases inhibitory controls on T cell activation and proliferation, inducing antitumor immunity in both preclinical and early clinical trials. We examined the mechanisms of action of anti-CTLA4 and a GM-CSF-transduced tumor cell vaccine (Gvax) and their impact on the balance of effector T cells (Teffs) and Tregs in an in vivo model of B16/BL6 melanoma. Tumor challenge increased the frequency of Tregs in lymph nodes, and untreated tumors became infiltrated by CD4+Foxp3- and CD4+Foxp3+ T cells but few CD8+ T cells. Anti-CTLA4 did not deplete Tregs or permanently impair their function but acted in a cell-intrinsic manner on both Tregs and Teffs, allowing them to expand, most likely in response to self antigen. While Gvax primed the tumor-reactive Teff compartment, inducing activation, tumor infiltration, and a delay in tumor growth, the combination with CTLA4 blockade induced greater infiltration and a striking change in the intratumor balance of Tregs and Teffs that directly correlated with tumor rejection. The data suggest that Tregs control both CD4+ and CD8+ T cell activity within the tumor, highlight the importance of the intratumor ratio of effectors to regulators, and demonstrate inversion of the ratio and correlation with tumor rejection during Gvax/anti-CTLA4 immunotherapy.
Mesh Headings (Keywords): Animals, Antigens, CD, Antigens, CD4, Antigens, CD8, Antigens, Differentiation, Cancer Vaccines, Cell Line, Tumor, Cell Proliferation, Forkhead Transcription Factors, Granulocyte-Macrophage Colony-Stimulating Factor, Immunotherapy, Lymph Nodes, Melanoma, Experimental, Mice, Mice, Inbred C57BL, T-Lymphocyte Subsets, T-Lymphocytes, Regulatory
Check for Full Text / PubMed Unique Identifier (PMID): 16778987
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