Timing of CSF-1/CSF-1R signaling blockade is critical to improving responses to CTLA-4 based immunotherapy
Timing of CSF-1/CSF-1R signaling blockade is critical to improving responses to CTLA-4 based immunotherapy
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DOI：
10.1080/2162402x.2016.1151595
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发表时间：
2016-01-01
期刊：
影响因子：
7.2
通讯作者：
Merghoub, Taha
中科院分区：
文献类型：
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作者：
Holmgaard, Rikke B.;Brachfeld, Alexandra;Merghoub, Taha
集落刺激因子-1（CSF-1）由多种癌症产生，并募集抑制抗肿瘤免疫的骨髓细胞，包括骨髓源性抑制细胞（MDSC）。在这里，我们发现CSF-1及其受体（CSF-1 R）经常在癌症患者的肿瘤中表达，并且这种表达与MDSC的肿瘤浸润相关。此外，我们证明，这些肿瘤浸润MDSC是高度免疫抑制，但可以重新编程后，CSF-1/CSF-1 R信号传导阻断体外抗肿瘤表型。支持这些发现，我们表明，使用抗CSF-1 R抗体抑制CSF-1/CSF-1 R信号传导可以调节体内小鼠肿瘤中MDSC的数量和功能。我们进一步发现，当与CTLA-4阻断疗法组合时，用抗CSF-1 R抗体治疗在多种肿瘤模型中诱导抗肿瘤T细胞应答和肿瘤消退。然而，这仅在CTLA-4阻断后或与CTLA-4阻断同时给药时发生，表明每次治疗干预的时机对于最佳抗肿瘤反应至关重要。重要的是，CTLA-4阻断后存在于鼠肿瘤内的MDSC显示出CSF-1 R的表达增加，并且能够抑制T细胞增殖，并且在用CTLA-4阻断免疫疗法治疗后，人肿瘤中的CSF-1/CSF-1 R表达没有减少。总之，我们的研究结果表明，表达CSF-1 R的MDSC可以靶向调节肿瘤微环境，CSF-1/CSF-1 R信号传导阻断的时机对于改善对基于检查点的免疫疗法的反应至关重要。意义：免疫抑制性骨髓细胞的浸润有助于肿瘤免疫逃逸，并可使患者对检查点阻断抗体的治疗干预产生耐药性或反应性降低。我们的数据表明，使用针对CSF-1 R的单克隆抗体阻断CSF-1/CSF-1 R信号传导可以调节肿瘤浸润免疫抑制性骨髓细胞的数量和功能。此外，我们的研究结果表明，重新编程骨髓反应可能是有效增强癌症免疫治疗的关键，为未来的临床测试提供了几种新的潜在联合疗法。对于临床试验设计来说，更重要的是，这些干预措施的时机对于实现改善的肿瘤保护至关重要。
Colony stimulating factor-1 (CSF-1) is produced by a variety of cancers and recruits myeloid cells that suppress antitumor immunity, including myeloid-derived suppressor cells (MDSCs.) Here, we show that both CSF-1 and its receptor (CSF-1R) are frequently expressed in tumors from cancer patients, and that this expression correlates with tumor-infiltration of MDSCs. Furthermore, we demonstrate that these tumor-infiltrating MDSCs are highly immunosuppressive but can be reprogrammed toward an antitumor phenotype in vitro upon CSF-1/CSF-1R signaling blockade. Supporting these findings, we show that inhibition of CSF-1/CSF-1R signaling using an anti-CSF-1R antibody can regulate both the number and the function of MDSCs in murine tumors in vivo. We further find that treatment with anti-CSF-1R antibody induces antitumor T-cell responses and tumor regression in multiple tumor models when combined with CTLA-4 blockade therapy. However, this occurs only when administered after or concurrent with CTLA-4 blockade, indicating that timing of each therapeutic intervention is critical for optimal antitumor responses. Importantly, MDSCs present within murine tumors after CTLA-4 blockade showed increased expression of CSF-1R and were capable of suppressing T cell proliferation, and CSF-1/CSF-1R expression in the human tumors was not reduced after treatment with CTLA-4 blockade immunotherapy. Taken together, our findings suggest that CSF-1R-expressing MDSCs can be targeted to modulate the tumor microenvironment and that timing of CSF-1/CSF-1R signaling blockade is critical to improving responses to checkpoint based immunotherapy.Significance: Infiltration by immunosuppressive myeloid cells contributes to tumor immune escape and can render patients resistant or less responsive to therapeutic intervention with checkpoint blocking antibodies. Our data demonstrate that blocking CSF-1/CSF-1R signaling using a monoclonal antibody directed to CSF-1R can regulate both the number and function of tumor-infiltrating immunosuppressive myeloid cells. In addition, our findings suggest that reprogramming myeloid responses may be a key in effectively enhancing cancer immunotherapy, offering several new potential combination therapies for future clinical testing. More importantly for clinical trial design, the timing of these interventions is critical to achieving improved tumor protection.