Inhibition of colony stimulating factor-1 receptor improves antitumor efficacy of BRAF inhibition.
Inhibition of colony stimulating factor-1 receptor improves antitumor efficacy of BRAF inhibition.
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DOI：
10.1186/s12885-015-1377-8
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发表时间：
2015-05-05
期刊：
影响因子：
3.8
通讯作者：
Ribas A
中科院分区：
文献类型：
--
作者：
Mok S;Tsoi J;Koya RC;Hu-Lieskovan S;West BL;Bollag G;Graeber TG;Ribas A
恶性黑色素瘤是一种侵袭性肿瘤类型，通常会对靶向治疗产生耐药性。肿瘤中集落刺激因子 1 (CSF-1) 的产生会招募骨髓细胞，例如 M2 极化巨噬细胞和骨髓源性抑制细胞 (MDSC)，从而形成免疫抑制肿瘤环境。我们使用 BRAFV600E 驱动的分泌 CSF-1 的黑色素瘤 SM1 的同基因小鼠模型来评估 CSF-1 受体 (CSF-1R) 抑制剂 PLX3397 提高致癌 BRAF 抑制剂维莫非尼 (vemurafenib) 抗肿瘤功效的能力。与单独治疗相比，BRAF 和 CSF-1R 联合抑制可产生更好的抗肿瘤反应。在接受 PLX3397 治疗的小鼠中，观察到肿瘤浸润骨髓细胞 (TIM) 显着减少。在此模型中，我们无法检测到 TIM 或 TIM 产生的促生存细胞因子的直接作用，这些细胞因子可能赋予 PLX4032（维莫非尼）耐药性。然而，PLX3397 治疗的巨噬细胞抑制作用与 PLX4032 介导的野生型 BRAF 表达免疫细胞的矛盾激活相结合，导致更多的肿瘤浸润淋巴细胞 (TIL)。 CD8+ T 细胞的耗竭消除了联合疗法的抗肿瘤反应。此外，从用 PLX3397 和 PLX4032 处理的 SM1 肿瘤中分离的 TIL 显示出更高的免疫增强活性。 BRAF 靶向治疗与 CSF-1R 阻断相结合，导致 SM1 黑色素瘤模型中 CD8 T 细胞反应增加，支持对 BRAFV600 突变转移性黑色素瘤患者的这种治疗组合的持续评估。本文的在线版本 (doi:10.1186/s12885-015-1377-8) 包含补充材料，可供授权用户使用。
Malignant melanoma is an aggressive tumor type that often develops drug resistance to targeted therapeutics. The production of colony stimulating factor 1 (CSF-1) in tumors recruits myeloid cells such as M2-polarized macrophages and myeloid derived suppressor cells (MDSC), leading to an immune suppressive tumor milieu. We used the syngeneic mouse model of BRAFV600E-driven melanoma SM1, which secretes CSF-1, to evaluate the ability of the CSF-1 receptor (CSF-1R) inhibitor PLX3397 to improve the antitumor efficacy of the oncogenic BRAF inhibitor vemurafenib. Combined BRAF and CSF-1R inhibition resulted in superior antitumor responses compared with either therapy alone. In mice receiving PLX3397 treatment, a dramatic reduction of tumor-infiltrating myeloid cells (TIM) was observed. In this model, we could not detect a direct effect of TIMs or pro-survival cytokines produced by TIMs that could confer resistance to PLX4032 (vemurafenib). However, the macrophage inhibitory effects of PLX3397 treatment in combination with the paradoxical activation of wild type BRAF-expressing immune cells mediated by PLX4032 resulted in more tumor-infiltrating lymphocytes (TIL). Depletion of CD8+ T-cells abrogated the antitumor response to the combination therapy. Furthermore, TILs isolated from SM1 tumors treated with PLX3397 and PLX4032 displayed higher immune potentiating activity. The combination of BRAF-targeted therapy with CSF-1R blockade resulted in increased CD8 T-cell responses in the SM1 melanoma model, supporting the ongoing evaluation of this therapeutic combination in patients with BRAFV600 mutant metastatic melanoma. The online version of this article (doi:10.1186/s12885-015-1377-8) contains supplementary material, which is available to authorized users.
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影响因子：
64.5
作者：
Heidorn SJ;Milagre C;Whittaker S;Nourry A;Niculescu-Duvas I;Dhomen N;Hussain J;Reis-Filho JS;Springer CJ;Pritchard C;Marais R
通讯作者：
Marais R
影响因子：
11.2
作者：
Koya RC;Mok S;Otte N;Blacketor KJ;Comin-Anduix B;Tumeh PC;Minasyan A;Graham NA;Graeber TG;Chodon T;Ribas A
通讯作者：
Ribas A
DOI：
10.1038/nrc3322
发表时间：
2012-10
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Gattinoni L;Klebanoff CA;Restifo NP
通讯作者：
Restifo NP
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
11.2
作者：
Gray-Schopfer, Vanessa C.;Karasarides, Maria;Marais, Richard
通讯作者：
Marais, Richard