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

J Clin Invest. 2006 Jul;116(7):1935-45. doi: 10.1172/JCI27745. Epub 2006 Jun 15.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD
  • Antigens, Differentiation* / immunology
  • Antigens, Differentiation* / therapeutic use
  • CD4 Antigens / immunology
  • CD8 Antigens / immunology
  • CTLA-4 Antigen
  • Cancer Vaccines / immunology
  • Cancer Vaccines / therapeutic use
  • Cell Line, Tumor
  • Cell Proliferation
  • Forkhead Transcription Factors / immunology
  • Granulocyte-Macrophage Colony-Stimulating Factor* / immunology
  • Granulocyte-Macrophage Colony-Stimulating Factor* / therapeutic use
  • Immunotherapy*
  • Lymph Nodes / cytology
  • Melanoma, Experimental* / immunology
  • Melanoma, Experimental* / therapy
  • Mice
  • Mice, Inbred C57BL
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocytes, Regulatory / immunology*


  • Antigens, CD
  • Antigens, Differentiation
  • CD4 Antigens
  • CD8 Antigens
  • CTLA-4 Antigen
  • Cancer Vaccines
  • Ctla4 protein, mouse
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Granulocyte-Macrophage Colony-Stimulating Factor