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Suppressing T cell motility induced by anti–CTLA-4 monotherapy improves antitumor effects
Maria Grazia Ruocco, … , Michael L. Dustin, Sandra Demaria
Maria Grazia Ruocco, … , Michael L. Dustin, Sandra Demaria
Published September 4, 2012
Citation Information: J Clin Invest. 2012;122(10):3718-3730. https://doi.org/10.1172/JCI61931.
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Research Article Oncology Article has an altmetric score of 2

Suppressing T cell motility induced by anti–CTLA-4 monotherapy improves antitumor effects

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Abstract

A promising strategy for cancer immunotherapy is to disrupt key pathways regulating immune tolerance, such as cytotoxic T lymphocyte–associated protein 4 (CTLA-4). However, the determinants of response to anti–CTLA-4 mAb treatment remain incompletely understood. In murine models, anti–CTLA-4 mAbs alone fail to induce effective immune responses to poorly immunogenic tumors but are successful when combined with additional interventions, including local ionizing radiation (IR) therapy. We employed an established model based on control of a mouse carcinoma cell line to study endogenous tumor-infiltrating CD8+ T lymphocytes (TILs) following treatment with the anti–CTLA-4 mAb 9H10. Alone, 9H10 monotherapy reversed the arrest of TILs with carcinoma cells in vivo. In contrast, the combination of 9H10 and IR restored MHC class I–dependent arrest. After implantation, the carcinoma cells had reduced expression of retinoic acid early inducible–1 (RAE-1), a ligand for natural killer cell group 2D (NKG2D) receptor. We found that RAE-1 expression was induced by IR in vivo and that anti-NKG2D mAb blocked the TIL arrest induced by IR/9H10 combination therapy. These results demonstrate that anti–CTLA-4 mAb therapy induces motility of TIL and that NKG2D ligation offsets this effect to enhance TILs arrest and antitumor activity.

Authors

Maria Grazia Ruocco, Karsten A. Pilones, Noriko Kawashima, Michael Cammer, Julie Huang, James S. Babb, Mengling Liu, Silvia C. Formenti, Michael L. Dustin, Sandra Demaria

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Figure 5

RAE-1/NKG2D interactions promote T cell arrest in the presence of TCR ligation and 9H10.

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RAE-1/NKG2D interactions promote T cell arrest in the presence of TCR li...
(A and B) In vitro analysis of T cell motility. Migration of preactivated CD8+ T cells over an ICAM-1–coated glass surface. Trajectories (A) and mean velocity (B) of individual CD8+ T cells stimulated with anti-CD3 and/or 9H10 in the absence or presence of RAE-1β, as indicated. Paths were tracked over time from confocal 2D time lapses. Each line corresponds to the path of an individual cell. Each dot represents the average speed of a cell tracked over 15 minutes. Data are representative of 3 independent experiments. Scale bar: 10 εm. (C and D) In vivo analysis of T cell motility. Cxcr6+/gfp mice were injected with 4T1-CFP cells on day 0 and left untreated or treated with IR+9H10 as described in Figure 2, and tumors were imaged by TPLSM on day 16 (Supplemental Videos 5 and 6). All mice received an i.p. injection of NKG2D blocking mAb CX5 30 minutes before imaging. (C) Trajectories of individual GFP+ TILs show that CX5 treatment led to increased migratory activity in mice treated with IR+9H10 but not in control mice. Scale bar: 30 εm. (D) Scatter plots showed increased speed and decreased arrest coefficient of TILs in the presence of NKG2D blockade in tumors of mice treated with IR+9H10. Data are derived from analysis of 3 mice per treatment group. Each data point represents a single cell, and red bars indicate mean values. **P < 0.005.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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