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

Authors: Quezada, S. A.; Peggs, K. S.; Curran, M. A.; Allison, J. P.
Article Title: 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.
Keywords: controlled study; unclassified drug; dose response; nonhuman; flow cytometry; lymph nodes; transcription factor foxp3; cd8+ t lymphocyte; cell proliferation; lymphocyte proliferation; forkhead transcription factors; animal cell; mouse; animals; mice; animal tissue; cytotoxic t lymphocyte antigen 4 antibody; melanoma; cell infiltration; granulocyte macrophage colony stimulating factor; animal experiment; animal model; in vivo study; antineoplastic activity; cell line, tumor; mice, inbred c57bl; cancer inhibition; regulatory t lymphocyte; immunotherapy; drug mechanism; cancer vaccines; t-lymphocytes, regulatory; lymph node; cd4+ t lymphocyte; melanoma, experimental; tumor immunity; effector cell; t-lymphocyte subsets; antigens, cd; tumor growth; tumor vaccine; antigens, cd4; tumor rejection; t lymphocyte activation; antigens, differentiation; antigens, cd8; granulocyte-macrophage colony-stimulating factor
Journal Title: Journal of Clinical Investigation
Volume: 116
Issue: 7
ISSN: 0021-9738
Publisher: American Society for Clinical Investigation  
Date Published: 2006-07-03
Start Page: 1935
End Page: 1945
Language: English
DOI: 10.1172/jci27745
PUBMED: 16778987
PROVIDER: scopus
PMCID: PMC1479425
Notes: --- - "Cited By (since 1996): 181" - "Export Date: 4 June 2012" - "CODEN: JCINA" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Karl Stuart Peggs
    11 Peggs
  2. James P Allison
    129 Allison
  3. Michael Andrew Curran
    15 Curran
  4. Sergio A Quezada
    14 Quezada