An osteopontin/CD44 immune checkpoint controls CD8+ T cell activation and tumor immune evasion
John D. Klement, … , Keiko Ozato, Kebin Liu
John D. Klement, … , Keiko Ozato, Kebin Liu
Published November 5, 2018
Citation Information: J Clin Invest. 2018;128(12):5549-5560. https://doi.org/10.1172/JCI123360.
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An osteopontin/CD44 immune checkpoint controls CD8+ T cell activation and tumor immune evasion

Abstract

Despite breakthroughs in immune checkpoint inhibitor (ICI) immunotherapy, not all human cancers respond to ICI immunotherapy and a large fraction of patients with the responsive types of cancers do not respond to current ICI immunotherapy. This clinical conundrum suggests that additional immune checkpoints exist. We report here that interferon regulatory factor 8 (IRF8) deficiency led to impairment of cytotoxic T lymphocyte (CTL) activation and allograft tumor tolerance. However, analysis of chimera mice with competitive reconstitution of WT and IRF8-KO bone marrow cells as well as mice with IRF8 deficiency only in T cells indicated that IRF8 plays no intrinsic role in CTL activation. Instead, IRF8 functioned as a repressor of osteopontin (OPN), the physiological ligand for CD44 on T cells, in CD11b+Ly6CloLy6G+ myeloid cells and OPN acted as a potent T cell suppressor. IRF8 bound to the Spp1 promoter to repress OPN expression in colon epithelial cells, and colon carcinoma exhibited decreased IRF8 and increased OPN expression. The elevated expression of OPN in human colon carcinoma was correlated with decreased patient survival. Our data indicate that myeloid and tumor cell–expressed OPN acts as an immune checkpoint to suppress T cell activation and confer host tumor immune tolerance.

Authors

John D. Klement, Amy V. Paschall, Priscilla S. Redd, Mohammed L. Ibrahim, Chunwan Lu, Dafeng Yang, Esteban Celis, Scott I. Abrams, Keiko Ozato, Kebin Liu

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Figure 5

IRF8 regulates antigen-specific CD8+ T cell differentiation and activation in a cell-extrinsic manner.

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IRF8 regulates antigen-specific CD8+ T cell differentiation and activati...
(A) Competitive mixed BM chimeras were created by adoptively transferring SJL (CD45.1+) WT whole BM cells with Irf8–/– BM cells into lethally irradiated C57BL/6×SJL) F1 recipients (CD45.1+CD45.2+). Peripheral blood cells were collected from WT and IRF8-KO mixed BM chimera mice, stained with CD45.1-, CD45.2-, CD4-, and CD8-specific mAbs, and analyzed by flow cytometry. Shown are representative plots of phenotypes of WT (CD45.1) and IRF8-KO (CD45.2) CD4+ and CD8+ T cells in the mixed BM chimeras. (B) The CD4+ and CD8+ cells from WT (CD45.1) and IRF8-KO (CD45.2) as shown in A were quantified. (C) Blood cells from WT and IRF8-KO mixed BM chimera mice were stained with CD45.1-, CD45.2-, CD8, CD44-, and CD62L-specific mAbs. CD8+ T cells were gated out for CD45.1 and CD45.2 cells. The WT and IRF8-KO CD8+ cells were then analyzed for CD44hi and CD62L+ cells. Representative plots of 1 of 3 mice are shown. (D) The percentage of CD44hi cells of the WT CD8+ and IRF8-KO CD8+ T cells was quantified. (E) WT (CD45.1) and IRF8-KO (CD45.2) mixed BM chimera mice were vaccinated with OVA peptide, followed by a boost with OVA peptide 14 days later. Peripheral blood was collected 7 days after boost and stained with MHCII-, CD8-, and OVA tetramer–specific antibodies. MHCII-CD8+ cells were gated for OVA tetramer+ cells. Shown are representative plots of OVA-specific WT and IRF8-KO CD8+ T cells. (F) The WT and IRF8-KO CD8+ OVA-specific T cells as shown in E were quantified.