Zoledronic acid overcomes chemoresistance and immunosuppression of malignant mesothelioma

Campia, Ivana; Kopecka, Joanna; Gazzano, Elena; Orecchia, Sara; Ghigo, Dario; Riganti, Chiara

doi:10.18632/oncotarget.2731

Cited by 35 publications

(49 citation statements)

References 49 publications

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“…2 The MPM microenvironment is rich of immunosuppressive and anergic immune cells, such as T-regulatory (Treg), granulocytic, and monocytic myeloid-derived suppressor cells (Gr-MDSC/Mo-MDSC) and M2-polarized tumor associated macrophages (TAMs), thattogether with soluble factors, such as cytokines, chemokines, and kynurenine, the product of 2,3-indoleamine dioxygenase enzymelead to a poor response to immune therapy. [3][4][5][6][7][8][9] Several cytokines accumulated in the pleural effusion of MPM patients promote the M2 polarization of macrophages. 10,11 M2/M3-macrophages and Gr-MDSC of MPM patients, as well as MPM cells reduce the proliferation of heterologous CD8a molecule-positive (CD8 þ ) T lymphocytes, by producing immunosuppressive mediators such as reactive oxygen species (ROS), nitric oxide (NO) and kynurenine.…”

Section: Introductionmentioning

confidence: 99%

“…10,11 M2/M3-macrophages and Gr-MDSC of MPM patients, as well as MPM cells reduce the proliferation of heterologous CD8a molecule-positive (CD8 þ ) T lymphocytes, by producing immunosuppressive mediators such as reactive oxygen species (ROS), nitric oxide (NO) and kynurenine. 3,4,7,10,[12][13][14] MDSCs are killed by active CD8 þ T lymphocytes, whereas either Tregs and MDSCs reduce CD8 þ T lymphocyte activity and memory CD8 þ T lymphocyte recruitment, inducing a vicious immunosuppressive circle. 4,6,[15][16][17][18] The high expression of immune checkpoints on T lymphocytes and of their ligands on MPM cell has another crucial role in the MPM-induced anergy of tumor-infiltrating lymphocytes (TILs).…”

Section: Introductionmentioning

confidence: 99%

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Potential Diagnostic and Prognostic Role of Microenvironment in Malignant Pleural Mesothelioma

Salaroglio

Kopecka

Napoli³

et al. 2019

Journal of Thoracic Oncology

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Introduction: A comprehensive analysis of the immune cell infiltrate collected from pleural fluid and from biopsy specimens of malignant pleural mesothelioma (MPM) may contribute to understanding the immune-evasion mechanisms related to tumor progression, aiding in differential diagnosis and potential prognostic stratification. Until now such approach has not routinely been verified. Methods:We enrolled 275 patients with an initial clinical diagnosis of pleural effusion. Specimens of pleural fluids and pleural biopsy samples used for the pathologic diagnosis and the immune phenotype analyses were blindly investigated by multiparametric flow cytometry. The results were analyzed using the Kruskal-Wallis test. The Kaplan-Meier and log-rank tests were used to correlate immune phenotype data with patients' outcome.Results: The cutoffs of intratumor T-regulatory (>1.1%) cells, M2-macrophages (>36%), granulocytic and monocytic myeloid-derived suppressor cells (MDSC; >5.1% and 4.2%, respectively), CD4 molecule-positive (CD4 þ ) programmed death 1-positive (PD-1 þ ) (>5.2%) and CD8 þ PD-1 þ (6.4%) cells, CD4 þ lymphocyte activating 3-positive (LAG-3 þ ) (>2.8% ) and CD8 þ LAG-3 þ (>2.8%) cells, CD4 þ T cell immunoglobulin and mucin domain 3positive (TIM-3 þ ) (>2.5%), and CD8 þ TIM-3 þ (>2.6%) cells discriminated MPM from pleuritis with 100% sensitivity and 89% specificity. The presence of intratumor MDSC contributed to the anergy of tumor-infiltrating lymphocytes.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Potential Diagnostic and Prognostic Role of Microenvironment in Malignant Pleural Mesothelioma

Salaroglio

Kopecka

Napoli³

et al. 2019

Journal of Thoracic Oncology

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“…[38, 39] In this study, we showed that ZA inhibited the proliferation and chemotactic migration of Treg cells, thereby improving the antitumor immune response. Recently, Ghigo et al found a similar effect of ZA, which down-regulated indoleamine 1,2 dioxygenase and enabled the proliferation of T cells and inhibited the expansion of Treg cells [40]. …”

Section: Discussionmentioning

confidence: 99%

Immune modulation of CD4+CD25+ regulatory T cells by zoledronic acid

et al. 2016

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BackgroundCD4+CD25+ regulatory T (Treg) cells suppress tumor immunity by inhibiting immune cells. Manipulation of Treg cells represents a new strategy for cancer treatment. Zoledronic acid (ZA), a nitrogen-containing bisphosphonate, inhibits the expression of receptor activator of nuclear factor kappa-B ligand (RANKL) on osteoblasts to inhibit osteoclastogenesis. In a mouse model of bisphosphonate-related osteonecrosis of the jaw, administration of ZA suppressed Treg-cell activity and activated inflammatory Th17 cells. However, the interaction between ZA and Treg cells remained unclear. This study investigated the immune modulation of Treg cells by ZA.MethodsFlow cytometry was used to analyze the phenotypic and immunosuppressive characteristics of Treg cells treated with ZA. Chemotactic migration was evaluated using transwell assays. Quantitative real-time PCR (qRT-PCR) was used to investigate the effect of ZA on the expression of suppressive molecules by Treg cells.ResultsProliferation of isolated Treg cells in culture was inhibited by ZA, although ZA did not induce apoptosis. qRT-PCR and flow cytometry showed that ZA significantly downregulated the expression of CCR4, CTLA4, PD-1 and RANKL on Treg cells. Chemotactic migration and immunosuppressive functions were also significantly attenuated in Treg cells pretreated with ZA, and these effects were dose-dependent. Co-culture with Treg cells significantly increased the migration rate of breast cancer cells, while pretreatment of Treg cells with ZA attenuated this effect.ConclusionsOur findings demonstrated that ZA acted as an immune modulator by significantly inhibiting the expansion, migration, immunosuppressive function and pro-metastatic ability of Treg cells. Immunomodulation of Treg cells by ZA represents a new strategy for cancer therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12865-016-0183-7) contains supplementary material, which is available to authorized users.

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“…First, ABCB1 limits the intracellular concentration of doxorubicin necessary to induce cell death. Second, ABCB1 inhibits the immune-sensitizing function of calreticulin [9,10]. The pharmacological inhibitors of ABCB1 did not reach satisfactory clinical efficacy, because of poor specificity and high toxicity.…”

Section: Introductionmentioning

confidence: 99%

“…Targeting signaling pathways up-regulating ABCB1 is an attractive alternative to inhibit this undruggable protein. For instance, lowering cholesterol and isoprenoid-dependent pathways decreases ABCB1 and produces chemo-immune-sensitization in different solid tumors [9,10].…”

Section: Introductionmentioning

confidence: 99%

ABCA1/ABCB1 Ratio Determines Chemo- and Immune-Sensitivity in Human Osteosarcoma

Belisario

Akman

Godel

et al. 2020

Cells

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The ATP Binding Cassette transporter B1 (ABCB1) induces chemoresistance in osteosarcoma, because it effluxes doxorubicin, reducing the intracellular accumulation, toxicity, and immunogenic cell death induced by the drug. The ATP Binding Cassette transporter A1 (ABCA1) effluxes isopentenyl pyrophosphate (IPP), a strong activator of anti-tumor Vγ9Vδ2 T-cells. Recruiting this population may represent an alternative strategy to rescue doxorubicin efficacy in ABCB1-expressing osteosarcoma. In this work, we analyzed how ABCA1 and ABCB1 are regulated in osteosarcoma, and if increasing the ABCA1-dependent activation of Vγ9Vδ2 T-cells could be an effective strategy against ABCB1-expressing osteosarcoma. We used 2D-cultured doxorubicin-sensitive human U-2OS and Saos-2 cells, their doxorubicin-resistant sublines (U-2OS/DX580 and Saos-2/DX580), and 3D cultures of U-2OS and Saos-2 cells. DX580-sublines and 3D cultures had higher levels of ABCB1 and higher resistance to doxorubicin than parental cells. Surprisingly, they had reduced ABCA1 levels, IPP efflux, and Vγ9Vδ2 T-cell-induced killing. In these chemo-immune-resistant cells, the Ras/Akt/mTOR axis inhibits the ABCA1-transcription induced by Liver X Receptor α (LXRα); Ras/ERK1/2/HIF-1α axis up-regulates ABCB1. Targeting the farnesylation of Ras with self-assembling nanoparticles encapsulating zoledronic acid (NZ) simultaneously inhibited both axes. In humanized mice, NZ reduced the growth of chemo-immune-resistant osteosarcomas, increased intratumor necro-apoptosis, and ABCA1/ABCB1 ratio and Vγ9Vδ2 T-cell infiltration. We suggest that the ABCB1 high ABCA1 low phenotype is indicative of chemo-immune-resistance. We propose aminobisphosphonates as new chemo-immune-sensitizing tools against drug-resistant osteosarcomas.

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Zoledronic acid overcomes chemoresistance and immunosuppression of malignant mesothelioma

Cited by 35 publications

References 49 publications

Potential Diagnostic and Prognostic Role of Microenvironment in Malignant Pleural Mesothelioma

Potential Diagnostic and Prognostic Role of Microenvironment in Malignant Pleural Mesothelioma

Immune modulation of CD4+CD25+ regulatory T cells by zoledronic acid

ABCA1/ABCB1 Ratio Determines Chemo- and Immune-Sensitivity in Human Osteosarcoma

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