An osteopontin/CD44 immune checkpoint controls CD8+ T cell activation and tumor immune evasion

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

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)5549-5560
Number of pages12
JournalJournal of Clinical Investigation
Volume128
Issue number12
DOIs
StatePublished - Dec 3 2018

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Tumor Escape
Osteopontin
T-Lymphocytes
Immunotherapy
Colon
Cytotoxic T-Lymphocytes
Neoplasms
Lymphocyte Activation
Carcinoma
Transplantation Tolerance
Immune Tolerance
Myeloid Cells
interferon regulatory factor-8
Bone Marrow Cells
Epithelial Cells
Ligands
Survival

ASJC Scopus subject areas

  • Medicine(all)

Cite this

An osteopontin/CD44 immune checkpoint controls CD8+ T cell activation and tumor immune evasion. / Klement, John D.; Paschall, Amy V.; Redd, Priscilla S.; Ibrahim, Mohammed L.; Lu, Chunwan; Yang, Dafeng; Celis, Esteban; Abrams, Scott I.; Ozato, Keiko; Liu, Kebin.

In: Journal of Clinical Investigation, Vol. 128, No. 12, 03.12.2018, p. 5549-5560.

Research output: Contribution to journalArticle

Klement, JD, Paschall, AV, Redd, PS, Ibrahim, ML, Lu, C, Yang, D, Celis, E, Abrams, SI, Ozato, K & Liu, K 2018, 'An osteopontin/CD44 immune checkpoint controls CD8+ T cell activation and tumor immune evasion', Journal of Clinical Investigation, vol. 128, no. 12, pp. 5549-5560. https://doi.org/10.1172/JCI123360
Klement, John D. ; Paschall, Amy V. ; Redd, Priscilla S. ; Ibrahim, Mohammed L. ; Lu, Chunwan ; Yang, Dafeng ; Celis, Esteban ; Abrams, Scott I. ; Ozato, Keiko ; Liu, Kebin. / An osteopontin/CD44 immune checkpoint controls CD8+ T cell activation and tumor immune evasion. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 12. pp. 5549-5560.
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