Therapeutic Targeting of LIF Overcomes Macrophage-mediated Immunosuppression of the Local Tumor Microenvironment.
Therapeutic Targeting of LIF Overcomes Macrophage-mediated Immunosuppression of the Local Tumor Microenvironment.
复制标题
LIF 的治疗靶向克服了巨噬细胞介导的局部肿瘤微环境的免疫抑制。
DOI：
10.1158/1078-0432.ccr-21-1888
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Fransson,Johan
中科院分区：
文献类型：
--
作者：
Hallett,RobinM;Bonfill-Teixidor,Ester;Iurlaro,Raffaella;Arias,Alexandra;Raman,Swetha;Bayliss,Peter;Egorova,Olga;Neva-Alejo,Almudena;McGray,AjRobert;Lau,Esther;Bosch,Alexandre;Beilschmidt,Melissa;Maetzel,Dorothea;Fransson,Johan
目的白血病抑制因子(LIF)是一种多功能细胞因子，在肿瘤发生、发展中起重要作用。表征LIF和临床阶段的LIF抑制剂将增加我们对LIF作为治疗靶点的理解。实验设计我们首先测试了LIF表达与代表调节肿瘤发生和进展的多个过程的转录签名的相关性。接下来，我们开发了一种高亲和力的治疗性抗体MSC-1，它可以有效地抑制LIF信号，并在具有免疫活性的癌症动物模型中进行了测试。结果LIF与肿瘤相关巨噬细胞()在跨越22个实体肿瘤指征的7,769个肿瘤样本中的特征有关。在人类肿瘤中，LIF受体在巨噬细胞内高表达，LIF治疗促使巨噬细胞获得免疫抑制能力。MSC-1通过结合与LIF上gp130受体结合位点重叠的表位，有效地抑制了LIF信号转导。MSC-1在小鼠同基因结肠癌模型中显示出单一治疗效果，并能驱动TAMS获得抗肿瘤和促炎作用。联合应用MSC-1和抗PD1可以在相当大比例的治疗小鼠中产生强烈的抗肿瘤反应和长期无瘤生存。结论总的来说，LIF是癌症免疫治疗的治疗靶点。
PurposeLeukemia inhibitory factor (LIF) is a multifunctional cytokine with numerous reported roles in cancer and is thought to drive tumor development and progression. Characterization of LIF and clinical-stage LIF inhibitors would increase our understanding of LIF as a therapeutic target.Experimental DesignWe first tested the association of LIF expression with transcript signatures representing multiple processes regulating tumor development and progression. Next, we developed MSC-1, a high-affinity therapeutic antibody that potently inhibits LIF signaling and tested it in immune competent animal models of cancer.ResultsLIF was associated with signatures of tumor-associated macrophages (TAM) across 7,769 tumor samples spanning 22 solid tumor indications. In human tumors, LIF receptor was highly expressed within the macrophage compartment and LIF treatment drove macrophages to acquire immunosuppressive capacity. MSC-1 potently inhibited LIF signaling by binding an epitope that overlaps with the gp130 receptor binding site on LIF. MSC-1 showed monotherapy efficacyin vivoand drove TAMs to acquire antitumor and proinflammatory function in syngeneic colon cancer mouse models. Combining MSC-1 with anti-PD1 leads to strong antitumor response and a long-term tumor-free survival in a significant proportion of treated mice.ConclusionsOverall, our findings highlight LIF as a therapeutic target for cancer immunotherapy.