Immune checkpoints PVR and PVRL2 are prognostic markers in AML and their blockade represents a new therapeutic option.
Immune checkpoints PVR and PVRL2 are prognostic markers in AML and their blockade represents a new therapeutic option.
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DOI：
10.1038/s41388-018-0288-y
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发表时间：
2018-09
期刊：
影响因子：
8
通讯作者：
Fiedler W
中科院分区：
文献类型：
--
作者：
Stamm H;Klingler F;Grossjohann EM;Muschhammer J;Vettorazzi E;Heuser M;Mock U;Thol F;Vohwinkel G;Latuske E;Bokemeyer C;Kischel R;Dos Santos C;Stienen S;Friedrich M;Lutteropp M;Nagorsen D;Wellbrock J;Fiedler W
免疫检查点是癌症治疗中有前途的靶点。最近，脊髓灰质炎病毒受体（PVR）和脊髓灰质炎病毒受体相关2（PVRL 2）已被确定为新的免疫检查点。在本研究中，我们显示急性髓性白血病（AML）细胞系和AML患者样品高度表达具有IG和ITIM结构域的T细胞免疫受体（TIGIT）配体PVR和PVRL 2。使用两个独立的患者队列，我们可以证明高PVR和PVRL 2表达与AML的不良结局相关。我们首次显示抗体阻断AML细胞系或原代AML细胞上的PVR或PVRL 2或阻断免疫细胞上的TIGIT在体外增加由PBMC或纯化的CD 3+细胞介导的抗白血病作用。BiTE®抗体构建体AMG 330针对白血病细胞的细胞溶解活性可通过阻断TIGIT-PVR/PVRL 2轴而进一步增强。这种增加的免疫反应性被免疫细胞增加的颗粒酶B分泌所抑制。在MV 4 -11细胞中采用CRISPR/Cas9介导的PVR和PVRL 2敲除，可以在体外重现抗体阻断的细胞毒性作用。在用人T细胞重建并移植MV 4 -11 PVR/PVRL 2敲除或野生型细胞的NSG小鼠中，观察到敲除细胞的存活延长。通过用AMG 330处理小鼠，可进一步延长这种生存获益。因此，用阻断抗体靶向TIGIT-PVR/PVRL 2轴可能代表AML中有前途的未来治疗选择。
Immune checkpoints are promising targets in cancer therapy. Recently, poliovirus receptor (PVR) and poliovirus receptor-related 2 (PVRL2) have been identified as novel immune checkpoints. In this investigation we show that acute myeloid leukemia (AML) cell lines and AML patient samples highly express the T-cell immunoreceptor with Ig and ITIM domains (TIGIT) ligands PVR and PVRL2. Using two independent patient cohorts, we could demonstrate that high PVR and PVRL2 expression correlates with poor outcome in AML. We show for the first time that antibody blockade of PVR or PVRL2 on AML cell lines or primary AML cells or TIGIT blockade on immune cells increases the anti-leukemic effects mediated by PBMCs or purified CD3+ cells in vitro. The cytolytic activity of the BiTE® antibody construct AMG 330 against leukemic cells could be further enhanced by blockade of the TIGIT-PVR/PVRL2 axis. This increased immune reactivity is paralleled by augmented secretion of Granzyme B by immune cells. Employing CRISPR/Cas9-mediated knockout of PVR and PVRL2 in MV4-11 cells, the cytotoxic effects of antibody blockade could be recapitulated in vitro. In NSG mice reconstituted with human T cells and transplanted with either MV4-11 PVR/PVRL2 knockout or wildtype cells, prolonged survival was observed for the knockout cells. This survival benefit could be further extended by treating the mice with AMG 330. Therefore, targeting the TIGIT-PVR/PVRL2 axis with blocking antibodies might represent a promising future therapeutic option in AML.
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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：
11.2
作者：
Le Mercier I;Chen W;Lines JL;Day M;Li J;Sergent P;Noelle RJ;Wang L
通讯作者：
Wang L
DOI：
10.1056/nejmoa1504030
发表时间：
2015-07-02
期刊：
The New England journal of medicine
影响因子：
--
作者：
Larkin J;Chiarion-Sileni V;Gonzalez R;Grob JJ;Cowey CL;Lao CD;Schadendorf D;Dummer R;Smylie M;Rutkowski P;Ferrucci PF;Hill A;Wagstaff J;Carlino MS;Haanen JB;Maio M;Marquez-Rodas I;McArthur GA;Ascierto PA;Long GV;Callahan MK;Postow MA;Grossmann K;Sznol M;Dreno B;Bastholt L;Yang A;Rollin LM;Horak C;Hodi FS;Wolchok JD
通讯作者：
Wolchok JD
影响因子：
5.7
作者：
Friedrich, Matthias;Henn, Anja;Rattel, Benno
通讯作者：
Rattel, Benno
影响因子：
50.3
作者：
Johnston, Robert J.;Comps-Agrar, Laetitia;Grogan, Jane L.
通讯作者：
Grogan, Jane L.