CCR8 marks highly suppressive Treg cells within tumours but is dispensable for their accumulation and suppressive function.
CCR8 marks highly suppressive Treg cells within tumours but is dispensable for their accumulation and suppressive function.
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DOI：
10.1111/imm.13337
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发表时间：
2021-08
期刊：
影响因子：
6.4
通讯作者：
Roychoudhuri R
中科院分区：
文献类型：
--
作者：
Whiteside SK;Grant FM;Gyori DS;Conti AG;Imianowski CJ;Kuo P;Nasrallah R;Sadiyah F;Lira SA;Tacke F;Eil RL;Burton OT;Dooley J;Liston A;Okkenhaug K;Yang J;Roychoudhuri R
CD4+ 调节性 T (Treg) 细胞依赖于转录因子 Foxp3，有助于肿瘤免疫抑制，但也是免疫稳态所必需的。人们有兴趣开发选择性靶向肿瘤内 Treg 细胞的免疫抑制功能而不破坏其全身抗炎功能的疗法。趋化因子（C-C 基序）受体 8 (CCR8) 的高水平表达可将肿瘤内的 Treg 细胞与全身淋巴组织中的 Treg 细胞区分开来。最近有人提出，使用阻断性抗 CCR8 抗体破坏 CCR8 功能会导致肿瘤内 Treg 细胞的积累减少，并破坏其免疫抑制功能。在这里，我们使用 Ccr8 −/− 小鼠，证明在同基因 MC38 结直肠腺癌和 B16 黑色素瘤背景下，CCR8 功能不是 Treg 细胞积累或免疫抑制所必需的。我们观察到肿瘤浸润 Treg 细胞上有高水平的 CCR8 表达，而这些细胞在 Ccr8 -/− 小鼠中被消除。高水平的 CCR8 标记细胞具有高水平的抑制功能。然而，虽然 Treg 细胞的系统性消融导致肿瘤负荷显着减轻，但皮下植入的肿瘤的生长并未受到系统性 CCR8 损失的影响。一致地，我们观察到全身性 CCR8 消融对肿瘤浸润 Treg 细胞的频率、表型和功能以及传统 T (Tconv) 功能的影响极小。这些发现表明，CCR8 并不是肿瘤内 Treg 细胞积累和免疫抑制功能所必需的，并且消耗 CCR8+ Treg 细胞而不是阻断 CCR8 功能是选择性免疫治疗更有希望的途径。人们有兴趣开发选择性靶向肿瘤内 Treg 细胞的免疫抑制功能而不破坏其全身抗炎功能的疗法。最近有人提出，使用阻断性抗 CCR8 抗体破坏 CCR8 功能会导致肿瘤内 Treg 细胞积聚减少，并破坏其免疫抑制功能。我们发现，CCR8 标记肿瘤内高度抑制性 Treg 细胞，但不是肿瘤内 Treg 细胞积聚和免疫抑制功能所必需的，这表明是消耗 CCR8+ Treg 细胞而不是阻断 CCR8 功能 是一种更有前景的选择性免疫治疗途径。
CD4+ regulatory T (Treg) cells, dependent upon the transcription factor Foxp3, contribute to tumour immunosuppression but are also required for immune homeostasis. There is interest in developing therapies that selectively target the immunosuppressive function of Treg cells within tumours without disrupting their systemic anti‐inflammatory function. High levels of expression of chemokine (C‐C motif) receptor 8 (CCR8) discriminate Treg cells within tumours from those found in systemic lymphoid tissues. It has recently been proposed that disruption of CCR8 function using blocking anti‐CCR8 antibodies results in reduced accumulation of Treg cells within tumours and disruption of their immunosuppressive function. Here, using Ccr8 −/− mice, we show that CCR8 function is not required for Treg cell accumulation or immunosuppression in the context of syngeneic MC38 colorectal adenocarcinoma and B16 melanoma tumours. We observed high levels of CCR8 expression on tumour‐infiltrating Treg cells which were abolished in Ccr8 −/− mice. High levels of CCR8 marked cells with high levels of suppressive function. However, whereas systemic ablation of Treg cells resulted in strikingly diminished tumour burden, growth of subcutaneously implanted tumours was unaffected by systemic CCR8 loss. Consistently, we observed minimal impact of systemic CCR8 ablation on the frequency, phenotype and function of tumour‐infiltrating Treg cells and conventional T (Tconv) function. These findings suggest that CCR8 is not required for Treg cell accumulation and immunosuppressive function within tumours and that depletion of CCR8+ Treg cells rather than blockade of CCR8 function is a more promising avenue for selective immunotherapy. There is interest in developing therapies that selectively target the immunosuppressive function of Treg cells within tumours without disrupting their systemic anti‐inflammatory function. It has recently been proposed that disruption of CCR8 function using blocking anti‐CCR8 antibodies results in reduced accumulation of Treg cells within tumours and disruption of their immunosuppressive function.We show that CCR8 marks highly suppressive Treg cells within tumours but is not required for Treg cell accumulation and immunosuppressive function within tumours, suggesting that depletion of CCR8+ Treg cells rather than blockade of CCR8 function is a more promising avenue for selective immunotherapy.
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影响因子：
32.4
作者：
Plitas, George;Konopacki, Catherine;Wu, Kenmin;Bos, Paula D.;Morrow, Monica;Putintseva, Ekaterina V.;Chudakov, Dmitriy M.;Rudensky, Alexander Y.
通讯作者：
Rudensky, Alexander Y.
DOI：
10.1084/jem.20130240
发表时间：
2013-09-23
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Islam SA;Ling MF;Leung J;Shreffler WG;Luster AD
通讯作者：
Luster AD
影响因子：
20.3
作者：
Coghill, James M.;Fowler, Kenneth A.;Serody, Jonathan S.
通讯作者：
Serody, Jonathan S.
DOI：
10.1084/jem.193.5.573
发表时间：
2001-03-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Chensue SW;Lukacs NW;Yang TY;Shang X;Frait KA;Kunkel SL;Kung T;Wiekowski MT;Hedrick JA;Cook DN;Zingoni A;Narula SK;Zlotnik A;Barrat FJ;O'Garra A;Napolitano M;Lira SA
通讯作者：
Lira SA
DOI：
10.1073/pnas.1621280114
发表时间：
2017-06-06
影响因子：
11.1
作者：
Barsheshet, Yiftah;Wildbaum, Gizi;Karin, Nathan
通讯作者：
Karin, Nathan