Tumor-Derived Osteopontin Suppresses Antitumor Immunity by Promoting Extramedullary Myelopoiesis

Kim, Min Jung; Jeon, Insu; Seo, Hyungseok; Park, Young Jun; Song, Boyeong; Lee, Kyoo A.; Jang, Yongwoo; Chung, Yeonseok; Kang, Chung Nam

doi:10.1158/0008-5472.can-14-1482

Cited by 42 publications

(34 citation statements)

References 51 publications

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“…In addition, recent studies indicated that OPN also had an immunosuppressive role in tumor milieu. Kim et al reported that tumor-derived OPN could lead to accumulation of peripheral myeloid-derived suppressor cells (MDSC), which were potent immunosuppressive cells [30]. These diverse mechanisms could potentially account for the results that OPN was associated with tumor aggressiveness in this meta-analysis.…”

Section: Discussionmentioning

confidence: 82%

Prognostic significance of osteopontin expression in gastric cancer: a meta-analysis

Gao

et al. 2016

Oncotarget

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BackgroundAccumulated studies have exploited the association between osteopontin (OPN) expression and survival of patients with gastric cancer (GC), however, the results were controversial. Thus, we performed a meta-analysis, aiming to investigate the prognostic role of OPN for GC patients and to explore the association between OPN and clinicalpathological features of GC.ResultsA total of ten studies involving 1775 patients were included in final meta-analysis. Of the included studies, nine were conducted on Asian patients and one was performed on Caucasian patients. Regarding OPN detection, immunohistochemistry (IHC) was used on tissue specimens in eight studies and enzyme linked immunosorbent assay (ELISA) was used on plasma specimens in two studies. The pooled data showed that high OPN expression was correlated with poor OS (HR = 1.59, 95% CI: 1.15–2.22, p = 0.006). Subgroup analyses demonstrated that OPN had enhanced prognostic value for Asian patients (HR = 1.64, 95% CI = 1.11–2.41, p = 0.012) and for patients receiving surgical resection (HR = 1.6, 95% CI = 1.04–2.48, p = 0.034). In addition, the results also showed that elevated OPN expression was associated with lymph node metastasis, TNM stage, depth of invasion, tumor size and distant metastasis in GC.MethodsRelevant studies were retrieved through PubMed, Embase and Web of Science. Combined hazard ratio (HR) and 95% confidence interval (CI) were calculated to assess the association between OPN and overall survival (OS). Subgroup analyses and publication bias were also conducted.ConclusionsOPN overexpression was correlated with poor OS and clinical features reflecting high aggressiveness in patients with GC. OPN was a promising prognostic biomarker for GC.

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Section: Discussionmentioning

confidence: 82%

Prognostic significance of osteopontin expression in gastric cancer: a meta-analysis

Gao

et al. 2016

Oncotarget

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“…We confirmed the trametinib-driven decrease in osteopontin secretion in separate ELISA experiments (Figure 7B). We focused on osteopontin because it has been reported to induce MDSCs expansion (25) and tumor recruitment of macrophages (24). Supporting the relevance of our proteomic analysis, the tumor-driven increase of osteopontin in plasma was abrogated by short-term (3 day) treatment with trametinib in Brpkp110-bearing mice (Figure 7C).…”

Section: Resultsmentioning

confidence: 99%

“…Among these, osteopontin has been implicated in the recruitment of macrophages into tumors (23) and its expression is positively correlated with CD204 + M2-like macrophages (24). Osteopontin secreted by tumor cells has also been reported to drive the expansion of MDSCs in the spleens of tumor-bearing mice through activation of the ERK1/2-MAPK pathway in myeloid progenitors (25). …”

Section: Introductionmentioning

confidence: 99%

Trametinib Drives T-cell–Dependent Control of KRAS-Mutated Tumors by Inhibiting Pathological Myelopoiesis

et al. 2016

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Targeted therapies elicit seemingly paradoxical and poorly understood effects on tumor immunity. Here we show that the MEK inhibitor trametinib abrogates cytokine-driven expansion of monocytic myeloid-derived suppressor cells (mMDSC) from human or mouse myeloid progenitors. MEK inhibition also reduced the production of the mMDSC chemotactic factor osteopontin by tumor cells. Together these effects reduced mMDSC accumulation in tumor-bearing hosts, limiting the outgrowth of K-Ras-driven breast tumors, even though trametinib largely failed to directly inhibit tumor cell proliferation. Accordingly, trametinib impeded tumor progression in vivo through a mechanism requiring CD8+ T cells, which was paradoxical given the drug’s reported ability to inhibit effector lymphocytes. Confirming our observations, adoptive transfer of tumor-derived mMDSC reversed the ability of trametinib to control tumor growth. Overall, our work showed how the effects of trametinib on immune cells could partly explain its effectiveness, distinct from its activity on tumor cells themselves. More broadly, by providing a more incisive view into how MEK inhibitors may act against tumors, our findings expand their potential uses to generally block monocytic MDSC expansion which occurs widely in cancers to drive their growth and progression.

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“…centrifugation step at room temperature, and the cells were subsequently incubated for an additional 18 h (for the B/Mo/αGC preparation this step was skipped). αGC (KRN7000, Enzo Life Science, Japan) was loaded into the prepared B cells and monocytes for NKT activation based on our previous studies20212251.…”

Section: Methodsmentioning

confidence: 99%

“…We have previously reported that an invariant natural killer T (NKT) cell ligand, alpha-galactosylceramide (αGC), loaded on a tumour antigen (tAg)-expressing B cell- and monocyte-based vaccine (B/Mo/tAg/αGC) elicited diverse anti-tumour immune responses202122. In this study, we found that B/Mo/tAg/αGC effectively eradicated otherwise resistant MHC class I-deficient tumour cells by activating NKT cells and inducing tumour antigen-specific cytotoxic T-cell responses.…”

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confidence: 99%

IL-21-mediated reversal of NK cell exhaustion facilitates anti-tumour immunity in MHC class I-deficient tumours

et al. 2017

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During cancer immunoediting, loss of major histocompatibility complex class I (MHC-I) in neoplasm contributes to the evasion of tumours from host immune system. Recent studies have demonstrated that most natural killer (NK) cells that are found in advanced cancers are defective, releasing the malignant MHC-I-deficient tumours from NK-cell-dependent immune control. Here, we show that a natural killer T (NKT)-cell-ligand-loaded tumour-antigen expressing antigen-presenting cell (APC)-based vaccine effectively eradicates these advanced tumours. During this process, we find that the co-expression of Tim-3 and PD-1 marks functionally exhausted NK cells in advanced tumours and that MHC-I downregulation in tumours is closely associated with the induction of NK-cell exhaustion in both tumour-bearing mice and cancer patients. Furthermore, the recovery of NK-cell function by IL-21 is critical for the anti-tumour effects of the vaccine against advanced tumours. These results reveal the process involved in the induction of NK-cell dysfunction in advanced cancers and provide a guidance for the development of strategies for cancer immunotherapy.

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Tumor-Derived Osteopontin Suppresses Antitumor Immunity by Promoting Extramedullary Myelopoiesis

Cited by 42 publications

References 51 publications

Prognostic significance of osteopontin expression in gastric cancer: a meta-analysis

Prognostic significance of osteopontin expression in gastric cancer: a meta-analysis

Trametinib Drives T-cell–Dependent Control of KRAS-Mutated Tumors by Inhibiting Pathological Myelopoiesis

IL-21-mediated reversal of NK cell exhaustion facilitates anti-tumour immunity in MHC class I-deficient tumours

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