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 (Treg) cells. Several recent reports, however, have suggested that these antibodies may deliver a "go" signal to effector T cells, thus interrupting TCR 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 treated with 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 (TDLNs) also increased. Because α-CTLA-4 Fab fragments had the same effect as the intact antibody, the higher T cell motility does not appear to be due to CTLA-4 inhibitory signaling but rather to the release of non-productive stable interactions between tumor-infiltrating T cells and tumor targets or APCs 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.
- Received May 29, 2014.
- Revision received July 2, 2014.
- Accepted July 2, 2014.
- Copyright © 2014, American Association for Cancer Research.