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

doi:10.1172/jci123360

Cited by 229 publications

(209 citation statements)

References 70 publications

(88 reference statements)

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“…Many previous studies have addressed managing the hypoxic tumor using HIF and PD-L1 inhibitors which resulted in promising outcomes (91,106). It is well established that boosting the CD8+ cell infiltration into the tumor niche can reverse immune evasion (107)(108)(109)(110). Results from our experiments using PX-478 and Durvalumab on 3D-O matrices confirm that reversing lymphocyte functional impairment is possible by either targeting HIF-1α or targeting inhibitory checkpoint pathways like PD-L1/PD-1.…”

Section: Immune Cell Infiltration Into 3d Matrices Has Been Observed supporting

confidence: 63%

Bioengineering a novel 3D in-vitro model to recreate physiological oxygen levels and tumor-immune interactions

Bhattacharya

Calar

Evans

et al. 2019

Preprint

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Oxygen deprivation within tumors is one of the most prevalent causes of resilient cancer cell survival and increased immune evasion in breast cancer (BCa). Current in vitro models do not adequately mimic physiological oxygen levels relevant to breast tissue and its tumor-immune interactions. Here, we propose an approach to engineer a three-dimensional (3D) model (named 3D engineered oxygen, 3D-O) that supports growth of BCa cells and generates physio-and pathophysiological oxygen levels. Low oxygen-induced changes within the 3D-O model supported known tumor hypoxia characteristics such as reduced BCa cell proliferation, increased extracellular matrix protein expression, increased extracellular vesicle secretion and enhanced immune surface marker expression on BCa cells. We further demonstrated that low oxygeninduced changes mimicked tumor-immune interactions leading to immune evasion mechanisms. CD8+ T cell infiltration was significantly impaired under pathophysiological oxygen levels andwe were able to establish that hypoxia inhibition re-sensitize BCa cells to cytotoxic CD8+ T cells.Therefore, our novel 3D-O model could serve as a promising platform for the evaluation of immunological events and as a drug-screening platform tool to overcome hypoxia-driven immune evasion.

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Section: Immune Cell Infiltration Into 3d Matrices Has Been Observed supporting

confidence: 63%

Bioengineering a novel 3D in-vitro model to recreate physiological oxygen levels and tumor-immune interactions

Bhattacharya

Calar

Evans

et al. 2019

Preprint

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“…OPN expression is suppressed by the binding of interferon regulatory factor 8 (IRF8) to the Spp1 promoter. Accordingly, IRF8 silencing in MDSCs during cell transformation is associated with OPN upregulation [107]. This study provides a perspective on OPN/CD44 interaction as an additional immune checkpoint that can be exploited to enhance immune responses against tumors.…”

Section: Dc-derived Opn In Tumor Progressionmentioning

confidence: 82%

Role of osteopontin in dendritic cell shaping of immune responses

Prete

Scutera

Sozzani

et al. 2019

Cytokine & Growth Factor Reviews

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Osteopontin (OPN) is a pleiotropic cytokine produced both by immune and non-immune cells and active on different cellular targets. OPN production has been associated with several pathological conditions, including autoimmune diseases (e.g. lupus, multiple sclerosis and rheumatoid arthritis) and cancer. Emerging evidence suggests that the role of OPN has been underestimated, as it seems to be working at multiple levels of immune regulation, such as the shaping of T cell effector responses, the regulation of the tumor microenvironment, and the functional interaction with mesenchymal stromal cells. In this context, dendritic cells (DCs) play a crucial role being both an important source and a cellular target for OPN action. DC family is composed by several cell subsets endowed with specific immune functions. OPN exerts its biological functions through multiple receptors and is produced in different intracellular and secreted forms. OPN production by DC subsets is emerging as a crucial mechanism of regulation in normal and pathological conditions and starts to be exploited as a therapeutic target. This review will focus on the role of DC-derived OPN in shaping immune response and on the complex role of this cytokines in the regulation in immune response.

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“…been shown to be induced in T cells following antigen stimulation, but its functions in this situation are less well understood. Klement et al demonstrated that IRF8 deficiency leads to abnormal generation of antigen-specific CD8 + T cells in vivo and results in an increased number of CD8 + T cells expressing high levels of CD44 (10). CD44 is a multifunctional transmembrane glycoprotein that was first identified as a receptor for hyaluronan and later shown to bind several other ligands, including OPN, collagen, fibronectin, chondroitin, and matrix metalloproteinases (13).…”

Section: Role Of Osteopontin In Immune Cell Regulation In the Tumor Mmentioning

confidence: 99%

“…Klement et al report that splenocytes from Irf8 -/mice express levels of OPN that viously uncharacterized tumor suppressor function of IRF8, by showing that IRF8 binds to the Spp1 promoter region to repress OPN expression in colon epithelial cells (10). However, during the transformation of colon epithelial cells into colon tumor cells, IRF8 expression is silenced and OPN is elevated, suggesting that tumor cells may use downregulation of IRF8 to upregulate OPN as a mechanism to suppress CD8 + T cellmediated anti tumor immunity ( Figure 1).…”

Section: The Journal Of Clinical Investigationmentioning

confidence: 99%

Osteopontin controls immunosuppression in the tumor microenvironment

Shurin¹

2018

Journal of Clinical Investigation

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

Cited by 229 publications

References 70 publications

Bioengineering a novel 3D in-vitro model to recreate physiological oxygen levels and tumor-immune interactions

Bioengineering a novel 3D in-vitro model to recreate physiological oxygen levels and tumor-immune interactions

Role of osteopontin in dendritic cell shaping of immune responses

Osteopontin controls immunosuppression in the tumor microenvironment

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