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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 6

Deletion of CD155 from host and tumor enhances the suppression of tumor progression.

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Deletion of CD155 from host and tumor enhances the suppression of tumor ...
(A) Experimental protocol for the induction of primary s.c. or lung metastases with control or Cd155-KO (sg2 and/or sg6) tumor cells in WT or Cd155–/– mice. (B) WT and Cd155–/– mice were injected i.v. with 1 × 105 B16F10 control, B16F10-Cd155–KO (sg2), or B16F10-Cd155–KO (sg6) cells (n = 5–6/group). Metastatic burden was quantified in the lungs by counting colonies on the lung surface 14 days after tumor cell inoculation (the experiment was performed once). (C) WT and Cd155–/– mice were injected i.v. with 5 × 105 LWT1 control or LWT1-Cd155–KO (sg6) cells (n = 7–10/group). Fourteen days after tumor inoculation, the metastatic burden was quantified in the lungs by counting colonies on the lung surface (the experiment was performed once). (D–F) WT and Cd155–/– mice were injected s.c. with 1 × 105 B16F10 control or B16F10-Cd155–KO (sg6) cells (n = 5/group) (D); 5 × 105 LWT1 control or LWT1-Cd155–KO (sg6) cells (n = 8–9/group) (E); or 5 × 105 MC38 control or MC38-Cd155–KO (sg6) cells (n = 5/group) (F), and tumor sizes were measured at the indicated time points. (G) WT and Cd155–/– mice were injected s.c. with 1 × 105 B16F10 control or B16F10-Cd155–KO (sg6) cells (n = 5/group). A dose of 250 μg cIg (clone 1-1) or anti–DNAM-1 (clone 480.1) mAb was injected on days –1, 0, and 7, relative to tumor inoculation (experiment was performed once). *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 2-way ANOVA. Data indicate the mean ± SEM and are representative of 3 experiments unless otherwise indicated. See also Supplemental Figure 6.

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

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