Inhibition of RANK signaling in breast cancer induces an anti-tumor immune response orchestrated by CD8+ T cells.
Inhibition of RANK signaling in breast cancer induces an anti-tumor immune response orchestrated by CD8+ T cells.
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乳腺癌中RANK信号传导的抑制诱导由CD8+ T细胞协调的抗肿瘤免疫应答。
DOI：
10.1038/s41467-020-20138-8
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发表时间：
2020-12-10
影响因子：
16.6
通讯作者：
González-Suárez E
中科院分区：
文献类型：
--
作者：
Gómez-Aleza C;Nguyen B;Yoldi G;Ciscar M;Barranco A;Hernández-Jiménez E;Maetens M;Salgado R;Zafeiroglou M;Pellegrini P;Venet D;Garaud S;Trinidad EM;Benítez S;Vuylsteke P;Polastro L;Wildiers H;Simon P;Lindeman G;Larsimont D;Van den Eynden G;Velghe C;Rothé F;Willard-Gallo K;Michiels S;Muñoz P;Walzer T;Planelles L;Penninger J;Azim HA Jr;Loi S;Piccart M;Sotiriou C;González-Suárez E
大多数乳腺癌表现出低免疫浸润，对免疫治疗无反应。我们假设抑制核因子-κB受体激活剂（RANK）信号通路可能增强免疫激活。在这里，我们报告了小鼠肿瘤细胞中RANK信号的丢失增加了白细胞、淋巴细胞和CD 8 + T细胞，并减少了巨噬细胞和中性粒细胞浸润。CD 8 + T细胞介导RANK丢失后观察到的减毒肿瘤表型，而中性粒细胞在表达RANK的肿瘤细胞的支持下诱导免疫抑制。RANKL抑制通过肿瘤细胞介导的效应增加免疫疗法在乳腺癌中的抗肿瘤作用。相比之下，II期D-BEYOND临床试验（NCT 01864798）中绝经前早期乳腺癌患者术前单药地舒单抗耐受性良好，可抑制RANK通路并增加肿瘤浸润淋巴细胞和CD 8 + T细胞。肿瘤中较高的RANK信号传导激活和基线时的血清RANKL水平预测了这些免疫调节作用。未观察到肿瘤细胞增殖（主要终点）或其他次要终点的变化。总体而言，我们的临床前和临床研究结果表明，肿瘤细胞利用RANK途径作为逃避免疫监视的机制，并支持使用RANK途径抑制剂来为腔内乳腺癌提供免疫治疗。核因子-κB（RANK）/RANK-配体（RANKL）信号传导受体激活剂调节肿瘤免疫串扰。在本文中，作者表明，全身性RANKL抑制促进早期乳腺癌患者的CD 8 + T细胞浸润，并且肿瘤细胞中RANK信号传导的丧失驱动了临床前模型中的T细胞依赖性抗肿瘤应答。
Most breast cancers exhibit low immune infiltration and are unresponsive to immunotherapy. We hypothesized that inhibition of the receptor activator of nuclear factor-κB (RANK) signaling pathway may enhance immune activation. Here we report that loss of RANK signaling in mouse tumor cells increases leukocytes, lymphocytes, and CD8+ T cells, and reduces macrophage and neutrophil infiltration. CD8+ T cells mediate the attenuated tumor phenotype observed upon RANK loss, whereas neutrophils, supported by RANK-expressing tumor cells, induce immunosuppression. RANKL inhibition increases the anti-tumor effect of immunotherapies in breast cancer through a tumor cell mediated effect. Comparably, pre-operative single-agent denosumab in premenopausal early-stage breast cancer patients from the Phase-II D-BEYOND clinical trial (NCT01864798) is well tolerated, inhibits RANK pathway and increases tumor infiltrating lymphocytes and CD8+ T cells. Higher RANK signaling activation in tumors and serum RANKL levels at baseline predict these immune-modulatory effects. No changes in tumor cell proliferation (primary endpoint) or other secondary endpoints are observed. Overall, our preclinical and clinical findings reveal that tumor cells exploit RANK pathway as a mechanism to evade immune surveillance and support the use of RANK pathway inhibitors to prime luminal breast cancer for immunotherapy. Receptor activator of nuclear factor-κB (RANK)/RANK-ligand (RANKL) signaling regulates the tumor-immune crosstalk. Here the authors show that systemic RANKL inhibition promotes CD8 + T cell infiltration in patients with early breast cancer and that loss of RANK signaling in tumor cells drives a T cell-dependent anti-tumor response in preclinical models.
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影响因子：
5.3
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