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 2

Tumor growth and metastasis are inhibited in Cd155–/– mice in a BM cell–dependent manner.

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Tumor growth and metastasis are inhibited in Cd155–/– mice in a BM cell–...
(A–C) WT and Cd155–/– mice were injected s.c. with 1 × 105 B16F10 cells (n = 6–7/group) (A) or 5 × 105 SM1WT1 cells (n = 7/group) (B), or 5 × 105 MC38 cells (n = 5–6/group) (C), and tumor sizes were measured at the indicated time points. (D and E) WT and Cd155–/– mice were challenged i.v. with 2 × 105 B16F10 cells (n = 8–11/group) (D) or 7.5 × 105 LWT1 cells (n = 6–7/group) (E), 2 weeks after tumor inoculation, and metastatic burden was quantified in the lungs by counting colonies on the lung surface. (F and G) WT and Cd155–/– mice were treated with 100 μg cIg, or 100 μg anti-CD8β (53.5.8, CD8+ T cell depletion), or 100 μg anti-CD4 (GK1.5, CD4+ T cell depletion) plus 100 μg anti-CD8β (53.5.8), or 50 μg anti-asGM1 (NK cell depletion) on days –1, 0, 7, and 14 for tumor growth, or on days –1, 0, and 7 for tumor metastasis relative to tumor inoculation. Mice were challenged s.c. with 1 × 105 B16F10 cells (n = 5–6/group; the experiment was performed once) (F), and tumor sizes were measured at the indicated time points, or mice were challenged i.v. with 7.5 × 105 LWT1 cells (n = 6/group) (G), and lung metastases were quantified 2 weeks after tumor inoculation. (H and J) Ptprca (CD45.1+) and Cd155–/– (CD45.2+) mice were irradiated twice (total radiation dose: 1,050 cGy/rad), and 5 × 106 BM cells from Ptprca or Cd155–/– mice were then i.v. injected into each irradiated mouse to construct BM chimeric mice (H). Mice were then challenged s.c. with 1 × 105 B16F10 (I) or i.v. with 2 × 105 B16F10 (J) cells, respectively (n = 10/group; the experiment was performed once for both I and J). Tumor sizes were measured at the indicated time points (I), and lung metastases were quantified 2 weeks after tumor inoculation (J). *P < 0.05, **P < 0.01, ***P < 0.001, 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 Figures 2 and 3.