Effective Treatment of Established Bone Metastases Can Be Achieved by Combinatorial Osteoclast Blockade and Depletion of Granulocytic Subsets.
Effective Treatment of Established Bone Metastases Can Be Achieved by Combinatorial Osteoclast Blockade and Depletion of Granulocytic Subsets.
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DOI：
10.1158/2326-6066.cir-21-0232
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发表时间：
2021-12
影响因子：
10.1
通讯作者：
Faccio R
中科院分区：
文献类型：
--
作者：
Capietto AH;Lee S;Clever D;Eul E;Ellis H;Ma CX;Faccio R
破骨细胞（OC）阻断已成功地减少肿瘤在骨的生长在临床前设置，但抗再吸收药物，如唑来膦酸（ZA），未能提高骨转移患者的总生存率，尽管改善骨骼并发症。为了解决这一未满足的临床需求，我们询问了除了OC之外还有哪些其他细胞调节骨中的肿瘤生长。由于髓源性抑制细胞（MDSC），表达CD 11b，Ly 6C和Ly 6 G标记物的异质群体，起源于骨髓并促进肿瘤进展，我们假设它们的积累阻碍了ZA的抗肿瘤作用。通过使用对OC阻断不敏感的骨转移小鼠模型，我们评估了使用抗Gr 1的MDSC耗竭在荷骨骼肺（LLC）、黑色素瘤（B16-F10）和乳腺（4 T1）肿瘤的小鼠中的抗肿瘤作用。与软组织肿瘤不同的是，抗Gr 1抗体不能减少骨转移，并导致骨髓驻留的CD 11b + Ly 6CintLy 6 Gint细胞在体外培养时分化为OC的矛盾积累。与单独使用每种药物相比，抗Gr 1介导的Ly 6 G+粒细胞MDSC耗竭联合ZA诱导的OC阻断可减少已建立的骨转移瘤的生长。与稳定型骨病患者相比，抗骨吸收治疗后进行性骨病的乳腺癌患者中CD 15+粒细胞群增加。我们提供的证据表明，抗吸收治疗不能减少骨转移的存在下，升高的粒细胞群体和有效的治疗已建立的骨转移，需要联合耗竭粒细胞和OC封锁。
Osteoclast (OC) blockade has been successful in reducing tumor growth in bone in pre-clinical settings, but anti-resorptive drugs, such as zoledronic acid (ZA), fail to improve the overall survival rate of patients with bone metastasis, despite ameliorating skeletal complications. To address this unmet clinical need, we interrogated what other cells modulated tumor growth in bone in addition to OCs. Because myeloid-derived suppressor cells (MDSCs), heterogeneous populations expressing CD11b, Ly6C, and Ly6G markers, originate in the bone marrow and promote tumor progression, we hypothesized that their accumulation hinders ZA anti-tumor effects. By using a murine model of bone metastasis insensitive to OC blockade, we assessed the anti-tumor effect of MDSC depletion using anti-Gr1 in mice bearing skeletal lung (LLC), melanoma (B16-F10), and mammary (4T1) tumors. Differently from soft tissue tumors, anti-Gr1 did not reduce bone metastases and led to the paradoxical accumulation of bone marrow-resident CD11b+Ly6CintLy6Gint cells that differentiated into OCs when cultured in vitro. Anti-Gr1-mediated depletion of Ly6G+ granulocytic MDSCs combined with ZA-induced OC blockade reduced growth of established skeletal metastases compared to each agent alone. CD15+ granulocytic populations were increased in breast cancer patients with progressive bone disease after anti-resorptive treatment compared to those with stable bone disease. We provide evidence that anti-resorptive therapies fail to reduce bone metastases in the presence of elevated granulocytic populations and that effective treatment of established skeletal metastases requires combinatorial depletion of granulocytes and OC blockade.