Cytotoxic T lymphocyte antigen-4 blockade enhances antitumor immunity by stimulating melanoma-specific T-cell motility.

Abstract

It is now clear that anti-CTLA-4 (α-CTLA-4) antibodies stimulate tumor immunity either by relieving inhibition of effector T-cell function or by depletion of regulatory T cells (Treg). Several recent reports, however, have suggested that these antibodies may deliver a "go" signal to effector T cells, thus interrupting T-cell receptor signaling and subsequent T-cell activation. We examined the behavior of melanoma-specific CD8+ pmel-1 T cells in the B16/BL6 mouse model using intravital microscopy. Pmel-1 velocities in progressively growing tumors were lower than their velocities in tumors given a therapeutic combination that included α-CTLA-4 antibodies, suggesting that successful immunotherapy correlates with greater T-cell motility. When α-CTLA-4 antibodies were injected during imaging, the velocities of pmel-1 T cells in tumor-draining lymph nodes also increased. Because α-CTLA-4 Fab fragments had the same effect as the intact antibody, the higher T-cell motility does not seem to be due to CTLA-4 inhibitory signaling but rather to the release of nonproductive stable interactions between tumor-infiltrating T cells and tumor targets or antigen-presenting cells subsequent to CTLA-4 blockade. This phenomenon resembles the recently described reversal of the antiviral T-cell motility paralysis by programmed death 1 (PD-1)-specific antibodies during T-cell exhaustion in persistent viral infections.

• Authors: Tsvetelina Pentcheva-Hoang, Tyler R Simpson, Welby Montalvo-Ortiz, James P Allison
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 2 Issue 10 Pg. 970-80 (Oct 2014) ISSN: 2326-6074 [Electronic] United States
• PMID: 25038199 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• CTLA-4 Antigen
• Cancer Vaccines
• GVAX vaccine

Topics

• Adoptive Transfer
• Animals
• CD8-Positive T-Lymphocytes (immunology)
• CTLA-4 Antigen (antagonists & inhibitors, immunology)
• Cancer Vaccines (immunology, therapeutic use)
• Cell Line, Tumor
• Cell Movement (immunology)
• Lymph Nodes (immunology)
• Lymphocytes, Tumor-Infiltrating (immunology)
• Melanoma, Experimental (immunology, therapy)
• Mice, Inbred C57BL
• T-Lymphocytes, Cytotoxic (immunology)