title: 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.affiliation: Department of Immunology, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Tsvetelina
authors.initials: T
authors.lastname: Pentcheva-Hoang
authors.affiliation: Department of Immunology, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Tyler R
authors.initials: TR
authors.lastname: Simpson
authors.affiliation: Department of Immunology, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Welby
authors.initials: W
authors.lastname: Montalvo-Ortiz
authors.affiliation: Department of Immunology, MD Anderson Cancer Center, Houston, Texas. jallison@mdanderson.org.
authors.forename: James P
authors.initials: JP
authors.lastname: Allison
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D008810:Mice, Inbred C57BL; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D060908:CTLA-4 Antigen; D019496:Cancer Vaccines; C000593794:GVAX vaccine