CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma.
CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma.
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DOI：
10.1016/j.ccell.2016.04.014
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发表时间：
2016-06-13
期刊：
影响因子：
50.3
通讯作者：
Morton JP
中科院分区：
文献类型：
--
作者：
Steele CW;Karim SA;Leach JDG;Bailey P;Upstill-Goddard R;Rishi L;Foth M;Bryson S;McDaid K;Wilson Z;Eberlein C;Candido JB;Clarke M;Nixon C;Connelly J;Jamieson N;Carter CR;Balkwill F;Chang DK;Evans TRJ;Strathdee D;Biankin AV;Nibbs RJB;Barry ST;Sansom OJ;Morton JP
CXCR2 被认为具有促进肿瘤和抑制肿瘤的特性。在这里，我们发现 CXCR2 信号在人类胰腺癌中上调，主要是在中性粒细胞/骨髓源性抑制细胞中，但在肿瘤细胞中很少。 CXCR2 的基因消除或抑制可以消除转移，但只有抑制才能减缓肿瘤发生。中性粒细胞/骨髓源性抑制细胞的消耗也抑制了转移，表明 CXCR2 在建立和维持转移生态位中发挥着关键作用。重要的是，CXCR2 的缺失或抑制可改善 T 细胞进入，并且联合抑制已患有疾病的小鼠的 CXCR2 和 PD1 可显着延长生存期。我们发现，骨髓区室中的 CXCR2 信号传导可以促进胰腺肿瘤发生，并且是胰腺癌转移所必需的，使其成为极佳的治疗靶点。 CXCR2 信号在人类胰腺癌的骨髓细胞中上调 Cxcr2 丢失可减少转移，抑制可延长小鼠的无瘤生存期 中性粒细胞/MDSC 在建立转移生态位中发挥关键作用 CXCR2 抑制可增强 T 细胞进入并赋予抗 PD1 疗法的敏感性 Steele 等。表明 CXCR2 在胰腺癌的免疫调节中很重要，抑制 CXCR2 可减少转移并改善对吉西他滨和抗 PD1 的反应。肽抑制剂（而非 Cxcr2 种系缺失）提高了生存率，揭示了对早期和晚期肿瘤的不同作用。
CXCR2 has been suggested to have both tumor-promoting and tumor-suppressive properties. Here we show that CXCR2 signaling is upregulated in human pancreatic cancer, predominantly in neutrophil/myeloid-derived suppressor cells, but rarely in tumor cells. Genetic ablation or inhibition of CXCR2 abrogated metastasis, but only inhibition slowed tumorigenesis. Depletion of neutrophils/myeloid-derived suppressor cells also suppressed metastasis suggesting a key role for CXCR2 in establishing and maintaining the metastatic niche. Importantly, loss or inhibition of CXCR2 improved T cell entry, and combined inhibition of CXCR2 and PD1 in mice with established disease significantly extended survival. We show that CXCR2 signaling in the myeloid compartment can promote pancreatic tumorigenesis and is required for pancreatic cancer metastasis, making it an excellent therapeutic target. CXCR2 signaling is upregulated in myeloid cells in human pancreatic cancer Cxcr2 loss reduces metastasis and inhibition prolongs tumor-free survival in mice Neutrophils/MDSCs play a key role in the establishment of the metastatic niche CXCR2 inhibition enhances T cell entry and confers sensitivity to anti-PD1 therapy Steele et al. show that CXCR2 is important in immune modulation of pancreatic cancer and that inhibition of CXCR2 reduces metastasis and improves response to gemcitabine and anti-PD1. Peptide inhibitor, but not germline deletion of Cxcr2, improved survival, revealing differential effects in early and late tumors.