Targeting the IGF-Axis Potentiates Immunotherapy for Pancreatic Ductal Adenocarcinoma Liver Metastases by Altering the Immunosuppressive Microenvironment.
Targeting the IGF-Axis Potentiates Immunotherapy for Pancreatic Ductal Adenocarcinoma Liver Metastases by Altering the Immunosuppressive Microenvironment.
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DOI：
10.1158/1535-7163.mct-20-0144
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发表时间：
2021-12
影响因子：
5.7
通讯作者：
Brodt P
中科院分区：
文献类型：
--
作者：
Hashimoto M;Konda JD;Perrino S;Celia Fernandez M;Lowy AM;Brodt P
胰腺导管腺癌（PDAC）是一种高度侵袭性的恶性肿瘤，对化疗耐药，肝转移发生率高，预后差。使用侵袭性PDAC的小鼠模型，我们在这里表明，在患有肝转移的小鼠中，用IGF-Trap（1型胰岛素样生长因子受体（IGF-IR）信号传导的抑制剂）治疗，深刻地改变了肝脏中的局部免疫抑制性肿瘤微环境，减少了髓源性抑制细胞的募集，逆转了先天性免疫细胞极化并抑制了转移性扩张。值得注意的是，我们发现用抗PD-1抗体进行免疫治疗也减少了实验性PDAC肝转移的生长，并且当与IGF-Trap治疗组合时，这种效果得到增强，导致T细胞应答的进一步增强。我们的研究结果表明，一方面通过IGF阻断双重靶向肝脏的促转移免疫微环境，另一方面逆转T细胞耗竭的组合免疫疗法可以在PDAC转移的管理中提供显著的治疗益处。
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy, resistant to chemotherapy and associated with high incidence of liver metastases and poor prognosis. Using murine models of aggressive PDAC, we show here that in mice bearing hepatic metastases, treatment with the IGF-Trap, an inhibitor of type 1 insulin like growth factor receptor (IGF-IR) signaling, profoundly altered the local, immunosuppressive tumor microenvironment in the liver, curtailing the recruitment of myeloid derived suppressor cells, reversing innate immune cell polarization and inhibiting metastatic expansion. Significantly, we found that immunotherapy with anti PD-1 antibodies also reduced the growth of experimental PDAC liver metastases, and this effect was enhanced when combined with IGF-Trap treatment, resulting in further potentiation of a T cell response. Our results show that a combinatorial immunotherapy based on dual targeting of the pro-metastatic immune microenvironment of the liver via IGF blockade, on one hand, and reversing T cell exhaustion on the other, can provide a significant therapeutic benefit in the management of PDAC metastases.
影响因子：
3.7
作者：
Shaw AK;Pickup MW;Chytil A;Aakre M;Owens P;Moses HL;Novitskiy SV
通讯作者：
Novitskiy SV