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. https://doi.org/10.1172/JCI123360.
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Categories: Research Article Immunology

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 1

IRF8 is essential for tumor rejection and antigen-specific CD8+ T cell activation.

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IRF8 is essential for tumor rejection and antigen-specific CD8+ T cell a...
(A) The BALB/c mouse–derived mammary carcinoma 4T1 cells (1 × 104 cells/mouse) were injected into the mammary gland of WT (C57BL6/J, n = 4) and IRF8-KO (C57BL/6, n = 3) mice. Mice were sacrificed at day 26 and dissected for examination of tumor presence. The image is representative of WT and IRF8-KO mice. The red arrow indicates location of 4T1 tumor. The right panel shows percentage of mice with tumor. Shown are representative images of 1 of 3 independent experiments. (B) Tumor growth was monitored over time. Each line represents the tumor growth kinetics of an individual mouse. (C–E) WT (n = 4) and IRF8-KO (n = 4) mice were vaccinated with OVA peptide, followed by a boost with the same peptide regime 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. Naive C57BL/6 mice were used as negative and gating controls (C). FSC-A, forward scatter–area. Shown are representative plots of one pair of WT and IRF8-KO mice from 1 of 2 independent experiments (D). The tetramer+ CD8+ T cells were quantified (E). (F) WT C57BL/6 and IRF8-KO BM cells were adoptively transferred into lethally irradiated C57BL/6 recipient mice to recreate chimera mice with IRF8 deficiency only in the hematopoietic cells. The chimera WT (n = 4) and IRF8-KO (n = 3) mice were vaccinated as in A–C and analyzed for OVA-specific CD8+ T cells. Shown are representative plots from one pair of mice. (G) Quantification of OVA-specific CD8+ T cells in WT and IRF8-KO chimera mice.