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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 Article has an altmetric score of 13

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

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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 7

Blockade of PD-1 pathway combined with CD155 deletion enhances tumor growth suppression.

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Blockade of PD-1 pathway combined with CD155 deletion enhances tumor gro...
(A) WT and Cd155–/– mice were injected s.c. with 1 × 106 MCA1956 cells (n = 10/group). cIg or anti–PD-1 mAb (50 μg) was injected on days 8, 12, 16, and 20, relative to tumor inoculation. (B) WT and Cd155–/– mice were injected s.c. with 1 × 105 MC38 cells (n = 5–6/group). cIg or anti-PD1 mAb (250 μg) was injected on days 8, 12, 16, and 20, relative to tumor inoculation. (C) WT and Cd155–/– mice were injected s.c. with 1 × 105 B16F10 control or B16F10-Cd155–KO (sg6) cells (n = 5/group). Mice were injected with 250 μg cIg or anti–PD-1/CTLA4 mAb on days 12, 15, 18, and 21, relative to tumor inoculation. (D) WT and Cd155–/– mice were injected s.c. with 1 × 105 B16F10 control or B16F10-Cd155–KO (sg6) cells (n = 5/group). cIg or anti–PD-1 and anti-CTLA4 mAbs (250 μg) were injected into WT mice with B16F10 control cells on days 8, 10, 12, and 14; WT mice with B16F10-Cd155–KO (sg6) cells on days 12, 14, 16, and 18; Cd155–/– mice with B16F10 control cells into on days 13, 15, 17, and 19; Cd155–/– mice with B16F10-Cd155–KO (sg6) cells on days 17, 19, 21, and 23, relative to tumor inoculation. (E) WT mice were injected s.c. with 1 × 105 B16F10 control (left) or B16F10-Cd155–KO (sg6) (right) cells (n = 5/group). A dose of 250 μg cIg, anti–PD-1 or anti-TIGIT and anti-CD96, or a combination of these mAbs was injected i.p. into WT mice with B16F10 control tumors on days 8, 10, 12, and 14 and into mice with B16F10-Cd155–KO (sg6) tumors on days 10, 12, 14, and 16, relative to tumor inoculation. (A–E) Tumor sizes were measured at the indicated time points. **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 2-way ANOVA. Data indicate the mean ± SEM. All experiments were performed once, except the experiment reflected in A, which was performed twice.

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

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