Combined Blockade of GARP:TGF-β1 and PD-1 Increases Infiltration of T Cells and Density of Pericyte-Covered GARP(+) Blood Vessels in Mouse MC38 Tumors.
Combined Blockade of GARP:TGF-β1 and PD-1 Increases Infiltration of T Cells and Density of Pericyte-Covered GARP(+) Blood Vessels in Mouse MC38 Tumors.
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联合阻断GARP：转化生长因子-β-1和PD-1可增加小鼠MC38肿瘤中T细胞的浸润和周细胞覆盖的GARP(+)血管密度。
DOI：
10.3389/fimmu.2021.704050
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发表时间：
2021
影响因子：
7.3
通讯作者：
Lucas S
中科院分区：
文献类型：
--
作者：
Bertrand C;Van Meerbeeck P;de Streel G;Vaherto-Bleeckx N;Benhaddi F;Rouaud L;Noël A;Coulie PG;van Baren N;Lucas S
当与抗PD-1组合时，针对GARP：TGF-β1复合物的单克隆抗体（mAb）比单独的抗PD-1更频繁地诱导CT 26和MC 38鼠肿瘤的免疫介导的排斥。在这两种类型的肿瘤中，抗GARP：TGF-β1 mAb的活性是由于阻断表达GARP的调节性T细胞的活性TGF-β1产生和免疫抑制。在CT 26肿瘤中，GARP：TGF-β1/PD-1联合阻断并没有增加T细胞的浸润，但确实增加了已经存在的抗肿瘤T细胞的效应功能。在这里，我们表明，相反，在MC 38中，组合GARP：TGF-β1/PD-1阻断增加了T细胞的浸润，这是T细胞从血管外渗增加的结果。出乎意料的是，组合的GARP：TGF-β1/PD-1阻断也增加了MC 38中被周细胞覆盖的GARP+血管的密度，但在CT 26肿瘤中没有。这似乎是因为抗GARP：TGF-β1通过阻断TGF-β1信号，促进血液内皮细胞增殖和粘附分子如E-选择素的表达。肿瘤内血管系统的致密化可能有助于增加T细胞浸润和GARP：TGF-β1/PD-1阻断在MC 38中的治疗功效。我们从MC 38和CT 26中的这些不同观察结果得出结论，GARP：TGF-β1和PD-1的组合阻断可以通过多种机制发挥抗肿瘤活性，包括肿瘤内血管系统的致密化和正常化、T细胞浸润到肿瘤中的增加以及肿瘤内肿瘤特异性T细胞的效应功能的增加。这可能对临床上选择可以从GARP：TGF-β1/PD-1联合阻断中获益的癌症患者很重要。
When combined with anti-PD-1, monoclonal antibodies (mAbs) against GARP:TGF-β1 complexes induced more frequent immune-mediated rejections of CT26 and MC38 murine tumors than anti-PD-1 alone. In both types of tumors, the activity of anti-GARP:TGF-β1 mAbs resulted from blocking active TGF-β1 production and immunosuppression by GARP-expressing regulatory T cells. In CT26 tumors, combined GARP:TGF-β1/PD-1 blockade did not augment the infiltration of T cells, but did increase the effector functions of already present anti-tumor T cells. Here we show that, in contrast, in MC38, combined GARP:TGF-β1/PD-1 blockade increased infiltration of T cells, as a result of increased extravasation of T cells from blood vessels. Unexpectedly, combined GARP:TGF-β1/PD-1 blockade also increased the density of GARP+ blood vessels covered by pericytes in MC38, but not in CT26 tumors. This appears to occur because anti-GARP:TGF-β1, by blocking TGF-β1 signals, favors the proliferation of and expression of adhesion molecules such as E-selectin by blood endothelial cells. The resulting densification of intratumoral blood vasculature probably contributes to increased T cell infiltration and to the therapeutic efficacy of GARP:TGF-β1/PD-1 blockade in MC38. We conclude from these distinct observations in MC38 and CT26, that the combined blockades of GARP:TGF-β1 and PD-1 can exert anti-tumor activity via multiple mechanisms, including the densification and normalization of intratumoral blood vasculature, the increase of T cell infiltration into the tumor and the increase of the effector functions of intratumoral tumor-specific T cells. This may prove important for the selection of cancer patients who could benefit from combined GARP:TGF-β1/PD-1 blockade in the clinics.
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影响因子：
3.7
作者：
Vermeersch E;Denorme F;Maes W;De Meyer SF;Vanhoorelbeke K;Edwards J;Shevach EM;Unutmaz D;Fujii H;Deckmyn H;Tersteeg C
通讯作者：
Tersteeg C
影响因子：
11.2
作者：
Shrimali RK;Yu Z;Theoret MR;Chinnasamy D;Restifo NP;Rosenberg SA
通讯作者：
Rosenberg SA
影响因子：
11.2
作者：
Metelli A;Wu BX;Fugle CW;Rachidi S;Sun S;Zhang Y;Wu J;Tomlinson S;Howe PH;Yang Y;Garrett-Mayer E;Liu B;Li Z
通讯作者：
Li Z
影响因子：
17.1
作者：
Allen E;Jabouille A;Rivera LB;Lodewijckx I;Missiaen R;Steri V;Feyen K;Tawney J;Hanahan D;Michael IP;Bergers G
通讯作者：
Bergers G
影响因子：
17.1
作者：
Cuende, Julia;Lienart, Stephanie;Lucas, Sophie
通讯作者：
Lucas, Sophie