CXCR4 inhibition in human pancreatic and colorectal cancers induces an integrated immune response.
CXCR4 inhibition in human pancreatic and colorectal cancers induces an integrated immune response.
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人胰腺癌和结直肠癌中的CXCR4抑制诱导综合免疫应答。
DOI：
10.1073/pnas.2013644117
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发表时间：
2020-11-17
影响因子：
11.1
通讯作者：
Jodrell DI
中科院分区：
文献类型：
--
作者：
Biasci D;Smoragiewicz M;Connell CM;Wang Z;Gao Y;Thaventhiran JED;Basu B;Magiera L;Johnson TI;Bax L;Gopinathan A;Isherwood C;Gallagher FA;Pawula M;Hudecova I;Gale D;Rosenfeld N;Barmpounakis P;Popa EC;Brais R;Godfrey E;Mir F;Richards FM;Fearon DT;Janowitz T;Jodrell DI
微卫星稳定型（MSS）胰腺癌（PDA）或结直肠癌（CRC）患者对T细胞检查点抑制剂免疫治疗无应答。一种可能的解释是，发现这些肿瘤中的癌细胞被趋化因子CXCL12包裹，刺激免疫细胞上的CXCR4 （CXCL12受体）抑制由这些细胞上的其他趋化因子受体介导的定向迁移。我们通过连续输注AMD3100/Plerixafor（一种CXCR4抑制剂）治疗患者7天来评估这些发现的相关性。通过转录组学分析比较治疗前和治疗结束时的转移性病变配对活检显示，AMD3100诱导了一种综合免疫反应，可预测对T细胞检查点抑制的临床反应。抑制趋化因子受体CXCR4联合阻断PD-1/PD-L1 T细胞检查点可诱导小鼠和人胰腺癌的T细胞浸润和抗癌反应。在这里，我们阐明了CXCR4抑制影响肿瘤免疫微环境的机制。在基于人类免疫细胞的趋化性实验中，我们发现cxcl12刺激的CXCR4分别抑制了由CXCR1、CXCR3、CXCR5、CXCR6和CCR2介导的定向迁移，这些趋化因子受体由参与综合免疫应答的所有免疫细胞类型表达。在一项实验性癌症医学研究中，通过连续输注小分子抑制剂AMD3100 (plerixafor) 1周抑制CXCR4可诱导综合免疫应答，通过对微卫星稳定型结直肠癌和胰腺癌患者转移灶配对活检的转录分析检测到这一点。这种综合免疫反应发生在免疫介导的非感染组织损伤的其他三个例子中：排斥肾同种异体移植物、临床对抗pd1抗体治疗有反应的黑色素瘤和微卫星不稳定结直肠癌。因此，CXCR4信号通路通过损害介导肿瘤内免疫细胞积聚的趋化因子受体的功能，在人胰腺导管腺癌和结直肠癌中引起免疫抑制。
Patients with microsatellite stable (MSS) pancreatic (PDA) or colorectal cancer (CRC) do not respond to immunotherapy with inhibitors of T cell checkpoints. A possible explanation is suggested by finding that cancer cells in these tumors are coated with the chemokine, CXCL12, and that stimulation of CXCR4, the CXCL12 receptor on immune cells, suppresses directed migration mediated by other chemokine receptors on these cells. We assessed the relevance of these findings by treating patients for seven days with continuous infusion of AMD3100/Plerixafor, a CXCR4 inhibitor. Comparison of pre- and end-of-treatment paired biopsies of metastatic lesions by transcriptomic analysis revealed that AMD3100 induced an integrated immune response that is predictive of a clinical response to T cell checkpoint inhibition. Inhibition of the chemokine receptor CXCR4 in combination with blockade of the PD-1/PD-L1 T cell checkpoint induces T cell infiltration and anticancer responses in murine and human pancreatic cancer. Here we elucidate the mechanism by which CXCR4 inhibition affects the tumor immune microenvironment. In human immune cell-based chemotaxis assays, we find that CXCL12-stimulated CXCR4 inhibits the directed migration mediated by CXCR1, CXCR3, CXCR5, CXCR6, and CCR2, respectively, chemokine receptors expressed by all of the immune cell types that participate in an integrated immune response. Inhibiting CXCR4 in an experimental cancer medicine study by 1-wk continuous infusion of the small-molecule inhibitor AMD3100 (plerixafor) induces an integrated immune response that is detected by transcriptional analysis of paired biopsies of metastases from patients with microsatellite stable colorectal and pancreatic cancer. This integrated immune response occurs in three other examples of immune-mediated damage to noninfected tissues: Rejecting renal allografts, melanomas clinically responding to anti-PD1 antibody therapy, and microsatellite instable colorectal cancers. Thus, signaling by CXCR4 causes immune suppression in human pancreatic ductal adenocarcinoma and colorectal cancer by impairing the function of the chemokine receptors that mediate the intratumoral accumulation of immune cells.
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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
影响因子：
64.8
作者：
Helmink BA;Reddy SM;Gao J;Zhang S;Basar R;Thakur R;Yizhak K;Sade-Feldman M;Blando J;Han G;Gopalakrishnan V;Xi Y;Zhao H;Amaria RN;Tawbi HA;Cogdill AP;Liu W;LeBleu VS;Kugeratski FG;Patel S;Davies MA;Hwu P;Lee JE;Gershenwald JE;Lucci A;Arora R;Woodman S;Keung EZ;Gaudreau PO;Reuben A;Spencer CN;Burton EM;Haydu LE;Lazar AJ;Zapassodi R;Hudgens CW;Ledesma DA;Ong S;Bailey M;Warren S;Rao D;Krijgsman O;Rozeman EA;Peeper D;Blank CU;Schumacher TN;Butterfield LH;Zelazowska MA;McBride KM;Kalluri R;Allison J;Petitprez F;Fridman WH;Sautès-Fridman C;Hacohen N;Rezvani K;Sharma P;Tetzlaff MT;Wang L;Wargo JA
通讯作者：
Wargo JA
影响因子：
15.8
作者：
Parkinson CA;Gale D;Piskorz AM;Biggs H;Hodgkin C;Addley H;Freeman S;Moyle P;Sala E;Sayal K;Hosking K;Gounaris I;Jimenez-Linan M;Earl HM;Qian W;Rosenfeld N;Brenton JD
通讯作者：
Brenton JD
DOI：
10.1164/rccm.201309-1611oc
发表时间：
2014-04-01
影响因子：
24.7
作者：
Germain, Claire;Gnjatic, Sacha;Dieu-Nosjean, Marie-Caroline
通讯作者：
Dieu-Nosjean, Marie-Caroline
影响因子：
64.8
作者：
Cabrita, Rita;Lauss, Martin;Jonsson, Goran
通讯作者：
Jonsson, Goran