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

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

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 6

Blocking NKG2D abrogates immune-mediated inhibition of the irradiated primary tumor in mice treated with IR+9H10 and reduces metastasis inhibition.

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Blocking NKG2D abrogates immune-mediated inhibition of the irradiated pr...
WT mice inoculated with parental 4T1 cells on day 0 (n = 7–13/group) were randomly assigned to different treatments, as indicated. IR was delivered in 2 fractions of 12 Gy to the s.c. tumors on day 12 and 13. Anti–CTLA-4 mAb 9H10 was given i.p. on days 15, 18, and 21. Anti-NKG2D mAb CX5 was given i.p. on days 15, 18, 21, 25, and 28. (A) Tumor volume is shown as the mean ± SEM at each time within each treatment group. CX5 by itself did not have any effect on tumor growth (P > 0.05, CX5 versus control). IR by itself caused significant tumor growth inhibition (P < 0.0005, IR versus control) that was not altered by CX5 (P = 0.4349, CX5+IR versus IR) but was significantly enhanced in the presence of 9H10 (P < 0.0005, IR+9H10 versus IR). The latter effect was completely abrogated by addition of CX5 (P = 0.1643, IR+9H10+CX5 versus IR). (B) The number of surface lung metastases was not significantly altered by IR or CX5 used alone (P > 0.05 versus control) or by IR in combination with CX5 (P > 0.05 versus control). IR+9H10 caused a significant inhibition of lung metastases (P < 0.005, IR+9H10 versus all other groups) that was partially abrogated by addition of CX5 (P < 0.05, IR+9H10 versus IR+9H10+CX5). Data shown are from 2 independent experiments combined. Bars indicate the mean ± SEM. *P < 0.05, **P < 0.005, ***P < 0.0005. (C) Images of lungs from representative animals in each treatment group, as indicated.