Targeting Suppressive Myeloid Cells Potentiates Checkpoint Inhibitors to Control Spontaneous Neuroblastoma

Mao, Yumeng; Eißler, Nina; Blanc, Katarina Le; Johnsen, John Inge; Kogner, Per; Kiessling, Rolf

doi:10.1158/1078-0432.ccr-15-1912

Cited by 115 publications

(109 citation statements)

References 54 publications

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“…We found that only the combination of the two therapies was effective in achieving efficient immune-cell activation resulting in strong antitumor efficacy in the transgenic neuroblastoma mouse model 20 . Similar to the observations made by Pyonteck et al., 31 BLZ945 single treatment did not abolish myeloid cells in the tumor, probably due to the presence of cytokines sustaining myeloid cell survival in the tumor microenvironment 20 . Our further analysis revealed that in addition to the removal of suppressive myeloid cells, repolarization of myeloid cells by enhancing CXCL9, 10, and 11 production presented an essential regulator.…”

Section: Discussionsupporting

confidence: 89%

“…In neuroblastoma, infiltration of TAMs was correlated to metastatic disease and worse prognosis 15 . Targeting suppressive myeloid cells through CSF-1R inhibition provides a promising approach for solid cancers, 20,31,32 particularly when combined with checkpoint inhibitors 20,33 . Several clinical programs are currently evaluating the safety and therapeutic values of this combinatorial approach (NCT02452424, NCT02526017, NCT02323191, and starting in October 2016 NCT02829723).…”

Section: Discussionmentioning

confidence: 99%

“…on days 0, 3, and 6. Alternatively, a highly selective CSF-1R tyrosine kinase inhibitor BLZ945 (Novartis) was dissolved in 20% Captisol® at 16 mg/mL and delivered daily by oral gavage at the dose of 200 mg/kg 20,31 in combination with the PD-1 blocking antibody. In some experiments, a CXCR3 blocking antibody (clone CXCR3-173, Bioxcell) was injected i.p.…”

Section: Methodsmentioning

confidence: 99%

“…A highly selective inhibitor (BLZ945) targeting CSF-1R signaling potently modulated suppressive myeloid cells 20 in transgenic mice developing spontaneous aggressive neuroblastoma (TH- MYCN model) 21,22 . Further, combining BLZ945 with checkpoint blockade antibodies against the PD-1/PD-L1 axis led to superior tumor control when compared to antibody treatment alone 20 . Antibody treatment alone showed marginal effects on suppressive myeloid cells, which could help explain the ineffectiveness of checkpoint blockade as a single treatment.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of myeloid cells by activated T cells determines the efficacy of PD-1 blockade

et al. 2016

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Removal of immuno-suppression has been reported to enhance antitumor immunity primed by checkpoint inhibitors. Although PD-1 blockade failed to control tumor growth in a transgenic murine neuroblastoma model, concurrent inhibition of colony stimulating factor 1 receptor (CSF-1R) by BLZ945 reprogrammed suppressive myeloid cells and significantly enhanced therapeutic effects. Microarray analysis of tumor tissues identified a significant increase of T-cell infiltration guided by myeloid cell-derived chemokines CXCL9, 10, and 11. Blocking the responsible chemokine receptor CXCR3 hampered T-cell infiltration and reduced antitumor efficacy of the combination therapy. Multivariate analysis of 59 immune-cell parameters in tumors and spleens detected the correlation between PD-L1-expressing myeloid cells and tumor burden. In vitro, anti-PD-1 antibody Nivolumab in combination with BLZ945 increased the activation of primary human T and NK cells. Importantly, we revealed a previously uncharacterized pathway, in which T cells secreted M-CSF upon PD-1 blockade, leading to enhanced suppressive capacity of monocytes by upregulation of PD-L1 and purinergic enzymes. In multiple datasets of neuroblastoma patients, gene expression of CD73 correlated strongly with myeloid cell markers CD163 and CSF-1R in neuroblastoma tumors, and associated with worse survival in high-risk patients. Altogether, our data reveal the dual role of activated T cells on myeloid cell functions and provide a rationale for the combination therapy of anti-PD-1 antibody with CSF-1R inhibitor.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Regulation of myeloid cells by activated T cells determines the efficacy of PD-1 blockade

et al. 2016

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“…It is associated with poor survival in various human cancer and CSF-1R (CSF-1 receptor) targeting strategies have been explored [23]. In NB, it has been shown that CSF-1R+ myeloid cells predict poor survival in patients and, as a consequence, combining CSF-1R inhibitor (BLZ945) with PD-1/PD-L1 blocking agents induce robust antitumor effects against established aggressive tumors in the TH-MYCN murine neuroblastoma model [24]. …”

Section: Cd171 (L1-cam) Is Another Abundant Cell Surface Molecule Expmentioning

confidence: 99%

Considerations for the Development of Innovative Therapies Against Aggressive Neuroblastoma: Immunotherapy and Twist1 Targeting

Shekarian¹,

Valsesia‐Wittmann²

2017

Neuroblastoma - Current State and Recent Updates

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Neuroblastoma (NB) is one of the major challenges of pediatric oncology with a 5-year survival rate of less than 40% despite intense therapy. The aggressiveness of the disease has been recently correlated to the degree of myeloid cells infiltrating the tumor. Together with the tumor cells and immunosuppressive cytokines (e.g., IL-10 and TGF-β), these cells hamper the generation of an efficient antitumor immune response and, therefore, favor tumor growth and metastasis. Novel therapeutic approaches are designed to target immune cells instead of cancer cells. To improve their efficacy, recent cancer immunotherapy strategies have focused on the depletion, blockade, or reprogramming of these tolerogenic immune effectors. Therefore, the principal clinical challenge is currently to identify therapeutic strategies which could overcome the primary and secondary resistances to these cancer immunotherapies. In this review, we discuss the dialogue of immune microenvironment of neuroblastoma and the immunotherapeutic strategies to cure neuroblastoma.

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Adoptive transfer of immature myeloid cells lacking NF‐κB p50 (p50‐IMC) impedes the growth of MHC‐matched high‐risk neuroblastoma

et al. 2021

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Targeting Suppressive Myeloid Cells Potentiates Checkpoint Inhibitors to Control Spontaneous Neuroblastoma

Cited by 115 publications

References 54 publications

Regulation of myeloid cells by activated T cells determines the efficacy of PD-1 blockade

Regulation of myeloid cells by activated T cells determines the efficacy of PD-1 blockade

Considerations for the Development of Innovative Therapies Against Aggressive Neuroblastoma: Immunotherapy and Twist1 Targeting

Adoptive transfer of immature myeloid cells lacking NF‐κB p50 (p50‐IMC) impedes the growth of MHC‐matched high‐risk neuroblastoma

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