CD155 loss enhances tumor suppression via combined host and tumor-intrinsic mechanisms
Xian-Yang Li, Indrajit Das, Ailin Lepletier, Venkateswar Addala, Tobias Bald, Kimberley Stannard, Deborah Barkauskas, Jing Liu, Amelia Roman Aguilera, Kazuyoshi Takeda, Matthias Braun, Kyohei Nakamura, Sebastien Jacquelin, Steven W. Lane, Michele W.L. Teng, William C. Dougall, Mark J. Smyth
Xian-Yang Li, Indrajit Das, Ailin Lepletier, Venkateswar Addala, Tobias Bald, Kimberley Stannard, Deborah Barkauskas, Jing Liu, Amelia Roman Aguilera, Kazuyoshi Takeda, Matthias Braun, Kyohei Nakamura, Sebastien Jacquelin, Steven W. Lane, Michele W.L. Teng, William C. Dougall, Mark J. Smyth
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Research Article Immunology

CD155 loss enhances tumor suppression via combined host and tumor-intrinsic mechanisms

Abstract

Critical immune-suppressive pathways beyond programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) require greater attention. Nectins and nectin-like molecules might be promising targets for immunotherapy, since they play critical roles in cell proliferation and migration and exert immunomodulatory functions in pathophysiological conditions. Here, we show CD155 expression in both malignant cells and tumor-infiltrating myeloid cells in humans and mice. Cd155–/– mice displayed reduced tumor growth and metastasis via DNAM-1 upregulation and enhanced effector function of CD8+ T and NK cells, respectively. CD155-deleted tumor cells also displayed slower tumor growth and reduced metastases, demonstrating the importance of a tumor-intrinsic role of CD155. CD155 absence on host and tumor cells exerted an even greater inhibition of tumor growth and metastasis. Blockade of PD-1 or both PD-1 and CTLA4 was more effective in settings in which CD155 was limiting, suggesting the clinical potential of cotargeting PD-L1 and CD155 function.

Authors

Xian-Yang Li, Indrajit Das, Ailin Lepletier, Venkateswar Addala, Tobias Bald, Kimberley Stannard, Deborah Barkauskas, Jing Liu, Amelia Roman Aguilera, Kazuyoshi Takeda, Matthias Braun, Kyohei Nakamura, Sebastien Jacquelin, Steven W. Lane, Michele W.L. Teng, William C. Dougall, Mark J. Smyth

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Figure 3

Inhibition of tumor growth and metastasis in Cd155–/– mice is DNAM-1 dependent.

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Inhibition of tumor growth and metastasis in Cd155–/– mice is DNAM-1 dep...
(A) DNAM-1, CD96, and TIGIT expression was analyzed on day 12 on tumor-infiltrating CD4+ T cells, CD8+ T cells, and NK cells after inoculation of 1 × 105 B16F10 cells in WT and CD155–/– mice (n = 5/group). The mean fluorescence intensity (MFI) is shown. (B) Tumor sizes were measured at the indicated time points for WT and Cd155–/– mice (n = 5–6/group) treated with 100 μg cIg, 100 μg anti-CD8β (clone 53.5.8), 250 μg anti-DNAM-1 (clone 480.1), or 50 μg anti-asGM1 on days –1, 0, 7, and 14, relative to inoculation of 1 × 105 B16F10 cells (the experiment was performed twice). (C) Splenocytes from naive C57BL/6 WT and Cd155–/– mice (n = 3) were stimulated with 1 μg/ml anti-CD3 and 2 μg/ml anti-CD28 for 24 hours, and the expression of IFN-γ on CD8+ T cells was analyzed by flow cytometry (data are representative of 2 experiments). (D) WT and Cd155–/– mice (n = 5/group) were injected i.v. with 1 × 105 B16F10 melanoma cells and treated on days –1, 0, and 7, relative to tumor inoculation with 250 μg cIg (clone 1-1), 250 μg anti–DNAM-1 (clone 480.1), or 50 μg anti-asGM1. Metastatic burden was quantified in the lungs by counting colonies on the lung surface 14 days after tumor cell inoculation (n = 5/group; the experiment was performed once). (E) NK cells from the spleens of naive C57BL/6 WT and Cd155–/– mice (n = 4) were purified and stimulated with the indicated concentrations of IL-12 and IL-18 for 24 hours, and the expression of IFN-γ on NK cells was analyzed by flow cytometry. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 1-tailed Mann-Whitney U test or 1-way ANOVA (A–E). Data indicate the mean ± SEM and are representative of 3 experiments unless otherwise indicated. See also Supplemental Figure 3.