Co-administration of RANKL and CTLA4 Antibodies Enhances Lymphocyte-Mediated Antitumor Immunity in Mice
Co-administration of RANKL and CTLA4 Antibodies Enhances Lymphocyte-Mediated Antitumor Immunity in Mice
复制标题
DOI：
10.1158/1078-0432.ccr-17-0606
复制
发表时间：
2017-10-01
影响因子：
11.5
通讯作者：
Smyth, Mark J.
中科院分区：
文献类型：
--
作者：
Ahern, Elizabeth;Harjunpaa, Heidi;Smyth, Mark J.
目的：在癌症治疗中需要新的免疫检查点抑制剂的合作伙伴来解决原发性和获得性耐药问题。RANKL和CTLA4联合阻断在抗肿瘤免疫中的作用已被最近的黑色素瘤病例报告所证实。在这里，我们为这种组合在小鼠癌症模型中提供了一个基本原理。实验设计：采用多种中和抗体和基因靶向小鼠，通过肿瘤浸润淋巴细胞分析、肿瘤生长和转移来检测RANKL和CTLA4联合阻断的疗效和机制。结果：RANKL阻断提高了抗ctla4单抗对实体瘤和实验转移瘤的疗效，小鼠IgG2a同型的调节性t细胞（Treg）消耗抗ctla4单抗的组合活性最大。最佳的组合依赖于激活Fc受体和淋巴细胞（NK细胞用于转移性疾病，CD8(+) T细胞主要用于皮下肿瘤控制）的存在，而单独抗rankl不需要FcR。抗rankl和抗ctla4后，实体肿瘤中t细胞浸润显著增加，同时t细胞效应功能（细胞因子多功能性）增加，抗rankl活性的发生与Treg消耗无关。RANKL在肿瘤中的表达主要在T细胞上，而表达RANKL的细胞主要是肿瘤相关巨噬细胞（TAM），在树突状细胞（DC）和髓源性抑制细胞（MDSC）上也有表达。结论：这些结果为进一步研究RANKL-RANK相互作用在肿瘤免疫中的作用提供了理论依据，并为开发人类临床试验中感兴趣的翻译标记物奠定了基础。(c) 2017 aacr。
Purpose: Novel partners for established immune checkpoint inhibitors in the treatment of cancer are needed to address the problems of primary and acquired resistance. The efficacy of combination RANKL and CTLA4 blockade in antitumor immunity has been suggested by recent case reports in melanoma. Here, we provide a rationale for this combination in mouse models of cancer.Experimental Design: The efficacy and mechanism of a combination of RANKL and CTLA4 blockade was examined by tumor-infiltrating lymphocyte analysis, tumor growth, and metastasis using a variety of neutralizing antibodies and gene-targeted mice.Results: RANKL blockade improved the efficacy of anti-CTLA4 mAbs against solid tumors and experimental metastases, with regulatory T-cell (Treg)-depleting anti-CTLA4 mAbs of the mouse IgG2a isotype showing greatest combinatorial activity. The optimal combination depended on the presence of activating Fc receptors and lymphocytes (NK cells for metastatic disease and predominantly CD8(+) T cells for subcutaneous tumor control), whereas anti-RANKL alone did not require FcR. The significantly higher T-cell infiltration into solid tumors post anti-RANKL and anti-CTLA4 was accompanied by increased T-cell effector function (cytokine polyfunctionality), and anti-RANKL activity occurred independently of Treg depletion. The majority of RANKL expression in tumors was on T cells whereas RANK-expressing cells were mostly tumor-associated macrophages (TAM), with some expression also observed on dendritic cells (DC) and myeloid-derived suppressor cells (MDSC).Conclusions: These results provide a rationale for the further investigation of RANKL-RANK interactions in tumor immunity and a basis for development of translational markers of interest in human clinical trials. (C) 2017 AACR.