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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

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 1

CD155 is expressed in malignant cells and tumor-infiltrating myeloid cells in human and mouse tumors.

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CD155 is expressed in malignant cells and tumor-infiltrating myeloid cel...
(A and B) Representative multiplexed IHC images of human primary cutaneous melanoma samples. CD155 (green) was distributed broadly within the carcinoma element of human melanoma, identified by HMB45 positivity (orange). Tumor-infiltrating myeloid cells were revealed by CD14 (red) or CD11c (yellow) positivity. The dotted line circumscribes HMB45+ tumor cells in a representative human melanoma TMA core. The merged image shows high colocalization of CD155 and HMB45. Scale bars: 200 μm (A) and 50 μm (B). (C) Colocalization of CD155 in tumor-infiltrating myeloid cells in human melanoma. CD11c (yellow) and CD14 (red) discriminated different populations of tumor-infiltrating cells, including CD11c+CD14– DCs (yellow arrows), CD11c+CD14+ myeloid cells (white arrows), and CD11c–CD14+ monocytes/macrophages (red arrows). CD155 staining (green) was colocalized within each of these myeloid populations, as indicated in the merged panel. Scale bar: 50 μm. (A–C) Nuclei were stained with DAPI (blue) in each panel. (D and E) WT mice were injected s.c. with 1 × 105 B16F10 cells (n = 5/group), and tumor samples were digested and analyzed on day 12. Tumor cells were gated by FSChiSSChiZombie-yellow–CD45.2– expression. (D) CD155 and PD-L1 expression on ex vivo B16F10 tumor cells is shown. (E) CD11b+CD11c+ and CD11b+CD11c– tumor-infiltrating myeloid cell populations were gated by FSCloSSCloZombie-yellow–CD45.2+ expression. CD155 and PD-L1 expression on these cells is shown. See also Supplemental Figures 1 and 2.

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

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