Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy.
Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy.
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DOI：
10.1126/scitranslmed.3007974
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发表时间：
2014-05-21
影响因子：
17.1
通讯作者：
Mackall CL
中科院分区：
文献类型：
--
作者：
Highfill SL;Cui Y;Giles AJ;Smith JP;Zhang H;Morse E;Kaplan RN;Mackall CL
宿主免疫系统的抑制在癌症进展中起主要作用。T细胞上的程序性死亡1（PD 1）的肿瘤信号传导和髓源性抑制细胞（MDSC）的扩增是肿瘤免疫逃逸的主要机制。我们试图在横纹肌肉瘤（RMS）中靶向这些通路，横纹肌肉瘤是儿童最常见的软组织肉瘤。小鼠RMS显示PD-L1的高表面表达，如果在肿瘤接种后早期开始抗PD 1，则抗PD 1可预防肿瘤生长;然而，延迟抗PD 1的益处有限。RMS诱导CXCR 2 + CD 11b + Ly 6 Ghi MDSC的稳健扩增，并且CXCR 2缺陷阻止CD 11b + Ly 6 Ghi MDSC运输至肿瘤。当MDSC的肿瘤运输被CXCR 2缺陷抑制时，或在抗CXCR 2单克隆抗体治疗后，延迟抗PD 1治疗诱导显著的抗肿瘤效应。因此，CXCR 2 + CD 11b + Ly 6 Ghi MDSC介导局部免疫抑制，这限制了检查点阻断在鼠RMS中的功效。人类小儿肉瘤也产生CXCR 2配体，包括CXCL 8。患有转移性小儿肉瘤的患者显示血清CXCR 2配体升高，并且升高的CXCL 8与该人群中的存活率降低相关。我们得出结论，MDSC在肿瘤床中的积累限制了检查点阻断在癌症中的功效。我们还鉴定了CXCR 2作为调节肿瘤免疫逃逸的新靶点，并提出了CXCR 2 + CD 11b + Ly 6 Ghi MDSC是儿科肉瘤中重要的抑制性髓系亚群的证据。这些发现提出了一种可转化的策略，通过防止MDSC运输到肿瘤部位来提高检查点阻断的功效。
Suppression of the host’s immune system plays a major role in cancer progression. Tumor signaling of programmed death 1 (PD1) on T cells and expansion of myeloid-derived suppressor cells (MDSCs) are major mechanisms of tumor immune escape. We sought to target these pathways in rhabdomyosarcoma (RMS), the most common soft tissue sarcoma of childhood. Murine RMS showed high surface expression of PD-L1, and anti-PD1 prevented tumor growth if initiated early after tumor inoculation; however, delayed anti-PD1 had limited benefit. RMS induced robust expansion of CXCR2+CD11b+Ly6Ghi MDSCs, and CXCR2 deficiency prevented CD11b+Ly6Ghi MDSC trafficking to the tumor. When tumor trafficking of MDSCs was inhibited by CXCR2 deficiency, or after anti-CXCR2 monoclonal antibody therapy, delayed anti-PD1 treatment induced significant antitumor effects. Thus, CXCR2+CD11b+Ly6Ghi MDSCs mediate local immunosuppression, which limits the efficacy of checkpoint blockade in murine RMS. Human pediatric sarcomas also produce CXCR2 ligands, including CXCL8. Patients with metastatic pediatric sarcomas display elevated serum CXCR2 ligands, and elevated CXCL8 is associated with diminished survival in this population. We conclude that accumulation of MDSCs in the tumor bed limits the efficacy of checkpoint blockade in cancer. We also identify CXCR2 as a novel target for modulating tumor immune escape and present evidence that CXCR2+CD11b+Ly6Ghi MDSCs are an important suppressive myeloid subset in pediatric sarcomas. These findings present a translatable strategy to improve the efficacy of checkpoint blockade by preventing trafficking of MDSCs to the tumor site.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
DOI：
10.1038/nrc3239
发表时间：
2012-03-22
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Pardoll DM
通讯作者：
Pardoll DM
单核细胞CCR2（+）髓样衍生的抑制细胞通过将活化的CD8 T细胞浸润限制在肿瘤微环境中，从而促进免疫逃逸。
影响因子：
11.2
作者：
Lesokhin AM;Hohl TM;Kitano S;Cortez C;Hirschhorn-Cymerman D;Avogadri F;Rizzuto GA;Lazarus JJ;Pamer EG;Houghton AN;Merghoub T;Wolchok JD
通讯作者：
Wolchok JD
影响因子：
20.3
作者：
Movahedi, Kiavash;Guilliams, Martin;Van Ginderachter, Jo A.
通讯作者：
Van Ginderachter, Jo A.
影响因子：
82.9
作者：
Mizukami, Y;Jo, WS;Chung, DC
通讯作者：
Chung, DC