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 (a-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 þ 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 a-CTLA-4 antibodies, suggesting that successful immunotherapy correlates with greater T-cell motility. When a-CTLA-4 antibodies were injected during imaging, the velocities of pmel-1 T cells in tumor-draining lymph nodes also increased. Because a-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. Cancer Immunol Res; 2(10); 970-80. Ó2014 AACR.

Checkpoint Blockade Immunotherapy Relies on T-bet but Not Eomes to Induce Effector Function in Tumor-Infiltrating CD8+ T Cells

“…For other genes like those encoding the chemokine CCL5 (RANTES) and its receptor CCR5, the contribution may be geared more toward T-cell migration, differentiation or the recruitment of other effector cells rather than direct tumor killing. Indeed, increased motility of melanoma-specific T cells was recently attributed to CTLA-4 blockade (26). To support these gene expression results, we analyzed T-bet, Eomes and CCR5 protein expression in transferred T cells from tumor-bearing Alb:Gag mice receiving checkpoint blockade.…”

Individual Motile CD4+ T Cells Can Participate in Efficient Multikilling through Conjugation to Multiple Tumor Cells

“…Second, the negative costimulatory molecules, PD1 and CTLA4 have opposing effects on T-cell motility both in vitro and in vivo 41,42 . Finally, recent intravital microscopy data from melanoma models in mice have demonstrated that successful therapeutic anti-CTLA4 treatment correlates with greater T-cell motility 43 .…”

In situ vaccination by radiotherapy to improve responses to anti-CTLA-4 treatment

“…Anti-CTLA-4 mAbs capable of mediating antibody-dependent cellular cytotoxicity (ADCC) effectively and selectively eliminated intratumoral Tregs, which express higher levels of CTLA-4 compared to circulating Tregs [84-86]. CTLA-4 ligation on effector T cells has also been shown to enhance motility of both CD4 and CD8 T cells [20, 87, 88]. Using CD8 T cells expressing a Pmel-1 transgenic TCR specific for a melanoma antigen Pentcheva-Hoang et al showed that increased motility was associated with tumor rejection, and hypothesized that anti-CTLA-4 may act by reversing motility paralysis of exhausted intratumoral T cells [87].…”

“…CTLA-4 ligation on effector T cells has also been shown to enhance motility of both CD4 and CD8 T cells [20, 87, 88]. Using CD8 T cells expressing a Pmel-1 transgenic TCR specific for a melanoma antigen Pentcheva-Hoang et al showed that increased motility was associated with tumor rejection, and hypothesized that anti-CTLA-4 may act by reversing motility paralysis of exhausted intratumoral T cells [87]. …”