CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells
Sergio A. Quezada, … , Michael A. Curran, James P. Allison
Sergio A. Quezada, … , Michael A. Curran, James P. Allison
Published July 3, 2006
Citation Information: J Clin Invest. 2006;116(7):1935-1945. https://doi.org/10.1172/JCI27745.
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Research Article Oncology

CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells

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.

Authors

Sergio A. Quezada, Karl S. Peggs, Michael A. Curran, James P. Allison

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Figure 2

Chronic CTLA4 blockade increases the frequency of Tregs in the lymph nodes without permanently altering their regulatory activity.

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Chronic CTLA4 blockade increases the frequency of Tregs in the lymph nod...
Mice were treated for a 2-week period with 100 μg anti-CTLA4 or control mouse Ig every other day. Lymph nodes were harvested and stained for CD4, CD25, and Foxp3. Data are presented as cytometric dot plots and graphically as percentages and absolute numbers of CD4+CD25+ (A), CD4+Foxp3+ (B), and CD4+Foxp3+ cells gated on the CD25– population (C). (D) CD4+CD25+ Tregs were isolated from mice treated/untreated with anti-CTLA4 for 2 weeks and tested for their ability to suppress naive CD4+CD25– T cell expansion in vitro in response to irradiated T cell–depleted splenocytes and 10 μg/ml anti-CD3. [3H]thymidine was added for the last 8 hours of a 72-hour culture. The numbers in the upper-right corners of the dot plots represent the percentage of cells in that quadrant, and the data are representative of 3 independent experiments with 3 independently analyzed mice/group.