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Inhibition of CSF-1R supports T-cell mediated melanoma therapy.

Sluijter M, van der Sluis TC, van der Velden PA, Versluis M, West BL, van der Burg SH, van Hall T - PLoS ONE (2014)

Bottom Line: The cytokine CSF-1 (or M-CSF) is an important factor of TAM recruitment and differentiation and several pharmacological agents targeting the CSF-1 receptor (CSF-1R) have been developed to regulate TAM in solid cancers.Elevated IFNγ production by T cells was observed in mice treated with the combination of PLX3397 and immunotherapy.These results support the combined use of CSF-1R inhibition with CD8 T cell immunotherapy, especially for macrophage-stimulating tumors.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, the Netherlands.

ABSTRACT
Tumor associated macrophages (TAM) can promote angiogenesis, invasiveness and immunosuppression. The cytokine CSF-1 (or M-CSF) is an important factor of TAM recruitment and differentiation and several pharmacological agents targeting the CSF-1 receptor (CSF-1R) have been developed to regulate TAM in solid cancers. We show that the kinase inhibitor PLX3397 strongly dampened the systemic and local accumulation of macrophages driven by B16F10 melanomas, without affecting Gr-1(+) myeloid derived suppressor cells. Removal of intratumoral macrophages was remarkably efficient and a modest, but statistically significant, delay in melanoma outgrowth was observed. Importantly, CSF-1R inhibition strongly enhanced tumor control by immunotherapy using tumor-specific CD8 T cells. Elevated IFNγ production by T cells was observed in mice treated with the combination of PLX3397 and immunotherapy. These results support the combined use of CSF-1R inhibition with CD8 T cell immunotherapy, especially for macrophage-stimulating tumors.

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Macrophage reduction slows down melanoma outgrowth.Kaplan-Meier survival curves from control and PLX3397-treated mice are shown of 26 mice per group, compiled from three independent experiments. Mice were sacrificed when tumors reached 1000 mm3. Statistical analyses was performed with log-rank test.
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pone-0104230-g003: Macrophage reduction slows down melanoma outgrowth.Kaplan-Meier survival curves from control and PLX3397-treated mice are shown of 26 mice per group, compiled from three independent experiments. Mice were sacrificed when tumors reached 1000 mm3. Statistical analyses was performed with log-rank test.

Mentions: We then examined B16F10 outgrowth during PLX3397 treatment. Kaplan-Meier analysis revealed a small but statistically significant survival benefit (p = 0.04) for mice treated with the CSF-1R inhibitor (Fig 3). These data suggested that macrophages harbored a tumor-promoting role in the B16F10 melanoma model. The rather small survival benefit of macrophage depletion surprised us, but might be explained by the relative increase of granulocytic myeloid cells, among which CD11b+Gr-1+ myeloid derived suppressor cells (MDSC) as found in many mouse tumor models [1], [13], [14]. Each tumor type sculpts their microenvironment in different directions and it remains to be evaluated which exact cues of the tumor drive myeloid differentiation pathways. We previously reported that tumor-secreted IL-6 and prostaglandin E2 are key in the differentiation to M2-type macrophages [15]. Nonetheless, a multitude of other soluble factors has been demonstrated to impose altered myeloid cell differentiation in the presence of solid tumors [1].


Inhibition of CSF-1R supports T-cell mediated melanoma therapy.

Sluijter M, van der Sluis TC, van der Velden PA, Versluis M, West BL, van der Burg SH, van Hall T - PLoS ONE (2014)

Macrophage reduction slows down melanoma outgrowth.Kaplan-Meier survival curves from control and PLX3397-treated mice are shown of 26 mice per group, compiled from three independent experiments. Mice were sacrificed when tumors reached 1000 mm3. Statistical analyses was performed with log-rank test.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4128661&req=5

pone-0104230-g003: Macrophage reduction slows down melanoma outgrowth.Kaplan-Meier survival curves from control and PLX3397-treated mice are shown of 26 mice per group, compiled from three independent experiments. Mice were sacrificed when tumors reached 1000 mm3. Statistical analyses was performed with log-rank test.
Mentions: We then examined B16F10 outgrowth during PLX3397 treatment. Kaplan-Meier analysis revealed a small but statistically significant survival benefit (p = 0.04) for mice treated with the CSF-1R inhibitor (Fig 3). These data suggested that macrophages harbored a tumor-promoting role in the B16F10 melanoma model. The rather small survival benefit of macrophage depletion surprised us, but might be explained by the relative increase of granulocytic myeloid cells, among which CD11b+Gr-1+ myeloid derived suppressor cells (MDSC) as found in many mouse tumor models [1], [13], [14]. Each tumor type sculpts their microenvironment in different directions and it remains to be evaluated which exact cues of the tumor drive myeloid differentiation pathways. We previously reported that tumor-secreted IL-6 and prostaglandin E2 are key in the differentiation to M2-type macrophages [15]. Nonetheless, a multitude of other soluble factors has been demonstrated to impose altered myeloid cell differentiation in the presence of solid tumors [1].

Bottom Line: The cytokine CSF-1 (or M-CSF) is an important factor of TAM recruitment and differentiation and several pharmacological agents targeting the CSF-1 receptor (CSF-1R) have been developed to regulate TAM in solid cancers.Elevated IFNγ production by T cells was observed in mice treated with the combination of PLX3397 and immunotherapy.These results support the combined use of CSF-1R inhibition with CD8 T cell immunotherapy, especially for macrophage-stimulating tumors.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, the Netherlands.

ABSTRACT
Tumor associated macrophages (TAM) can promote angiogenesis, invasiveness and immunosuppression. The cytokine CSF-1 (or M-CSF) is an important factor of TAM recruitment and differentiation and several pharmacological agents targeting the CSF-1 receptor (CSF-1R) have been developed to regulate TAM in solid cancers. We show that the kinase inhibitor PLX3397 strongly dampened the systemic and local accumulation of macrophages driven by B16F10 melanomas, without affecting Gr-1(+) myeloid derived suppressor cells. Removal of intratumoral macrophages was remarkably efficient and a modest, but statistically significant, delay in melanoma outgrowth was observed. Importantly, CSF-1R inhibition strongly enhanced tumor control by immunotherapy using tumor-specific CD8 T cells. Elevated IFNγ production by T cells was observed in mice treated with the combination of PLX3397 and immunotherapy. These results support the combined use of CSF-1R inhibition with CD8 T cell immunotherapy, especially for macrophage-stimulating tumors.

Show MeSH
Related in: MedlinePlus