Control of tumor-associated macrophages and T cells in glioblastoma via AHR and CD39

被引：460

作者：

Takenaka, Maisa C. ^{[1
]}

Gabriely, Galina ^{[1
]}

Rothhammer, Veit ^{[1
]}

Mascanfroni, Ivan D. ^{[1
]}

Wheeler, Michael A. ^{[1
]}

Chao, Chun-Cheih ^{[1
]}

Gutierrez-Vazquez, Cristina ^{[1
]}

Kenison, Jessica ^{[1
]}

Tjon, Emily C. ^{[1
]}

Barroso, Andreia ^{[1
]}

Vandeventer, Tyler ^{[1
]}

de Lima, Kalil Alves ^{[1
]}

Rothweiler, Sonja ^{[2
,3
,4
]}

Mayo, Lior ^{[1
]}

Ghannam, Soufiene ^{[5
]}

Zandee, Stephanie ^{[5
]}

Healy, Luke ^{[6
]}

Sherr, David ^{[7
]}

Farez, Mauricio F. ^{[8
,9
]}

Pratt, Alexandre ^{[5
]}

Antel, Jack ^{[6
]}

Reardon, David A. ^{[10
]}

Zhang, Hailei ^{[11
]}

Robson, Simon C. ^{[2
,3
,4
]}

Getz, Gad ^{[11
]}

Weiner, Howard L. ^{[1
]}

Quintana, Francisco J. ^{[1
,11
]}

机构：

[1] Harvard Med Sch, Ann Romney Ctr Neurol Dis, Brigham & Womens Hosp, Boston, MA 02115 USA

[2] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Gastroenterol, Boston, MA 02115 USA

[3] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Hepatol, Boston, MA 02115 USA

[4] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Transplantat, Boston, MA 02115 USA

[5] Univ Montreal, Neuroimmunol Res Lab, Ctr Excellence Neur, Dept Neurosci, Montreal, PQ, Canada

[6] McGill Univ, Dept Neurol & Neurosurg, Neuroimmunol Unit, Montreal Neurol Inst, Montreal, PQ, Canada

[7] Boston Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA

[8] Raul Carrea Inst Neurol Res FLENI, Ctr Res Neuroimmunol Dis CIEN, Buenos Aires, DF, Argentina

[9] Raul Carrea Inst Neurol Res FLENI, Ctr Epidemiol Biostat & Publ Hlth CEBES, Buenos Aires, DF, Argentina

[10] Brigham & Womens Hosp, Dana Farber Canc Inst, Ctr Neurooncol, 75 Francis St, Boston, MA 02115 USA

[11] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

来源：

NATURE NEUROSCIENCE | 2019年 / 22卷 / 05期

基金：

美国国家卫生研究院;

关键词：

STRONG PREDICTOR; RECEPTOR; EXPRESSION; POLARIZATION; AUTOIMMUNITY; PROGRESSION; ACTIVATION; PI3K-GAMMA; MICROGLIA; SUPPRESS;

D O I：

10.1038/s41593-019-0370-y

中图分类号：

Q189 [神经科学];

学科分类号：

071006 [神经生物学];

摘要：

Tumor-associated macrophages (TAMs) play an important role in the immune response to cancer, but the mechanisms by which the tumor microenvironment controls TAMs and T cell immunity are not completely understood. Here we report that kynurenine produced by glioblastoma cells activates aryl hydrocarbon receptor (AHR) in TAMs to modulate their function and T cell immunity. AHR promotes CCR2 expression, driving TAM recruitment in response to CCL2. AHR also drives the expression of KLF4 and suppresses NF-kappa B activation in TAMs. Finally, AHR drives the expression of the ectonucleotidase CD39 in TAMs, which promotes CD8(+) T cell dysfunction by producing adenosine in cooperation with CD73. In humans, the expression of AHR and CD39 was highest in grade 4 glioma, and high AHR expression was associated with poor prognosis. In summary, AHR and CD39 expressed in TAMs participate in the regulation of the immune response in glioblastoma and constitute potential targets for immunotherapy.

引用

页码：729 / +

页数：15

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