PLX3397 inhibits the accumulation of intra-tumoral macrophages and improves BET inhibitor efficacy in melanoma.

PLX3397 inhibits the accumulation of intra-tumoral macrophages and improves BET inhibitor efficacy in melanoma.

Publication date: Nov 06, 2019

Bromodomain and extra terminal inhibitors (BETi) delay tumor growth, in part, through tumor cell intrinsic alterations and initiation of anti-tumor CD8+ T cell responses. By contrast, BETi effects on pro-tumoral immune responses remain unclear. Here, we show that the next generation BETi, PLX51107, delayed tumor growth to differing degrees in Braf V600E melanoma syngeneic mouse models. These differential responses were associated with the influx of tumor-associated macrophages during BETi treatment. Tumors that were poorly responsive to PLX51107 showed increased influx of colony stimulating factor-1 receptor (CSF-1R)-positive tumor-associated macrophages. We depleted CSF-1R+ tumor-associated macrophages with the CSF-1R inhibitor, PLX3397, in combination with PLX51107. Treatment with PLX3397 enhanced the efficacy of PLX51107 in poorly responsive Braf V600E syngeneic melanomas in vivo. These findings suggest that tumor-associated macrophage accumulation limits BETi efficacy and that co-treatment with PLX3397 can improve response to PLX51107, offering a potential novel combination therapy for metastatic melanoma patients.

Erkes, D.A., , Rosenbaum, Field, C.O., , Chervoneva, Villanueva, J., and Aplin, A.E. PLX3397 inhibits the accumulation of intra-tumoral macrophages and improves BET inhibitor efficacy in melanoma. 24686. 2019 Pigment Cell Melanoma Res.

Concepts Keywords
Bromodomain Branches of biology
CD8 Medicine
Combination Therapy Cell biology
Differential Immune system
Inhibitor Macrophages
Macrophage Melanoma
Macrophages RTT
Melanoma BRAF
Melanomas Vemurafenib
Pigment
Tumor

Semantics

Type Source Name
gene UNIPROT DNER
disease MESH melanoma
disease DOID melanoma
pathway BSID Melanoma
disease MESH tumor
disease MESH growth
gene UNIPROT BRAF
gene UNIPROT CSF1R

Original Article

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