Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies Journal Article
| Authors: | Peggs, K. S.; Quezada, S. A.; Chambers, C. A.; Korman, A. J.; Allison, J. P. |
| Article Title: | Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies |
| Abstract: | Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a critical negative regulator of immune responses. Uniquely among known inhibitory receptors, its genetic ablation results in a fulminating and fatal lymphoproliferative disorder. This central regulatory role led to the development of antibodies designed to block CTLA-4 activity in vivo, aiming to enhance immune responses against cancer. Despite their preclinical efficacy and promising clinical activity against late stage metastatic melanoma, the critical cellular targets for their activity remains unclear. In particular, debate has focused on whether the effector T cell (Teff) or regulatory T cell (T reg cell) compartment is the primary target of antibody-mediated blockade. We developed a mouse expressing human instead of mouse CTLA-4, allowing us to evaluate the independent contributions of CTLA-4 blockade of each T cell compartment during cancer immunotherapy in an in vivo model of mouse melanoma. The data show that although blockade on effector cells significantly improves tumor protection, unicompartmental blockade on regulatory cells completely fails to enhance antitumor responses. However, concomitant blockade of both compartments leads to a synergistic effect and maximal antitumor activity. We conclude that the combination of direct enhancement of Teff cell function and concomitant inhibition of T reg cell activity through blockade of CTLA-4 on both cell types is essential for mediating the full therapeutic effects of anti-CTLA-4 antibodies during cancer immunotherapy. © 2009 Peggs et al. |
| Keywords: | controlled study; nonhuman; animal cell; mouse; animals; mice; mice, knockout; cytotoxic t lymphocyte antigen 4 antibody; cancer immunotherapy; melanoma; animal experiment; animal model; antineoplastic activity; cell line, tumor; mice, inbred c57bl; transgenic mouse; mice, transgenic; regulatory t lymphocyte; immunotherapy; t-lymphocytes, regulatory; recombinant proteins; melanoma, experimental; effector cell; t-lymphocyte subsets; antigens, cd; cytotoxic t lymphocyte antigen 4; antibodies, neoplasm; immunosuppression |
| Journal Title: | Journal of Experimental Medicine |
| Volume: | 206 |
| Issue: | 8 |
| ISSN: | 0022-1007 |
| Publisher: | Rockefeller University Press |
| Date Published: | 2009-08-03 |
| Start Page: | 1717 |
| End Page: | 1725 |
| Language: | English |
| DOI: | 10.1084/jem.20082492 |
| PUBMED: | 19581407 |
| PROVIDER: | scopus |
| PMCID: | PMC2722174 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 31" - "Export Date: 30 November 2010" - "CODEN: JEMEA" - "Source: Scopus" |
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