CD155 loss enhances tumor suppression via combined host and tumor-intrinsic mechanisms
Xian-Yang Li, … , William C. Dougall, Mark J. Smyth
Xian-Yang Li, … , William C. Dougall, Mark J. Smyth
Published May 14, 2018
Citation Information: J Clin Invest. 2018;128(6):2613-2625. https://doi.org/10.1172/JCI98769.
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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 5

Tumor-intrinsic CD155 is critical for tumor cell migration and survival.

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Tumor-intrinsic CD155 is critical for tumor cell migration and survival....
(A and B) WT and Rag2–/–γc–/– mice were injected s.c. with 2 × 105 B16F10 control or B16F10-Cd155–KO (sg2 and sg6) cells (n = 6/group) (A), or 5 × 105 LWT1 control or LWT1-Cd155–KO (sg2 and sg6) cells (n = 5–6/group) (B), and tumor sizes were measured at the indicated time points (the experiment was performed once). (C and D) Rag2–/–γc–/– mice were injected i.v. with 5 × 104 B16F10 control or B16F10-Cd155–KO (sg6) cells (n = 5/group) (C), or 1 × 105 LWT1 control or LWT1-Cd155–KO (sg6) cells (n = 6/group) (D), and the metastatic burden was quantified in the lungs by counting colonies on the lung surface 14 days after tumor cell inoculation. (E) B16F10 control and B16F10-Cd155–KO (sg6) cells (200 cells/well; n = 3/group) were cultured in 6-well plates for 6 days and stained with crystal violet to assess relative CFU. Images of the colonies of B16F10 control and B16F10-CD155–KO (sg6) cells are shown, and the relative CFU was assessed (representative of 3 experiments). (F and G) B16F10 control or B16F10-CD155–KO (sg6) cells (1 × 105 cells/well) were cultured in 96-well plates. Wounds were made, and wound-healing images were monitored and analyzed, and the percentage of relative wound closure was determined. (H and I) B16F10 control and B16F10-CD155–KO (sg6) cells (1 × 105 cells/well) were cultured in 24-well plates under normoxic or hypoxic conditions (n = 4/group) (H) or in media supplemented with 10% or 1% serum (n = 4/group) (I), and apoptosis was evaluated 48 hours later with annexin V and 7-AAD. (H and I) Graphs show the representative rate of cell death. *P < 0.05, **P < 0.01, and ****P < 0.0001, by 1-tailed Mann–Whitney U test or 2-way ANOVA. Data indicate the mean ± SEM and are representative of 3 experiments unless otherwise indicated. See also Supplemental Figure 4D and Supplemental Figure 5.