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 4

Deletion of tumor CD155 decreases tumor growth and metastasis.

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Deletion of tumor CD155 decreases tumor growth and metastasis. (A–D) WT ...
(A–D) WT mice were injected s.c. with 1 × 105 B16F10 control or B16F10-Cd155–KO (sg2 and sg6) cells (n = 6/group) (A); 5 × 105 LWT1 control or LWT1-Cd155–KO (sg2 and sg6) cells (n = 5–6/group) (B); 5 × 105 MC38 control or MC38-Cd155–KO (sg2 and sg6) cells (n = 5/group) (C); or 1 × 106 MCA1956 control or MCA1956-Cd155–KO (sg6) cells (n = 5/group) (D), and tumor sizes were measured at the indicated time points. (E–G) WT mice were injected i.v. with 2 × 105 B16F10 control or B16F10-Cd155–KO (sg6) cells (n = 5–6/group) (E); 7.5 × 105 LWT1 control or LWT1-Cd155–KO (sg2 and sg6) cells (n = 4–7/group) (F); or 2 × 105 MC38 control or MC38-Cd155–KO (sg2 and sg6) cells (n = 7/group) (G). Metastatic burden in the lungs was quantified by counting colonies on the lung surface 14 days after tumor inoculation. (H and I) Female BALB/c WT mice were injected into the mammary fat pad with 5 × 104 4T1.2 control or 4T1.2-Cd155–KO cells, and tumors were resected on day 14. In 1 group, the metastatic burden was quantified in the lungs by counting colonies on the lung surface on day 30 (n = 9/group) (H), and in another group, the survival was monitored (I) (n = 14–20/group; experiment was performed twice). *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 Figure 4.