Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors

被引：505

作者：

Chongsathidkiet, Pakawat ^{[1
,2
,3
]}

Jackson, Christina ^{[4
]}

Koyama, Shohei ^{[5
]}

Loebel, Franziska ^{[6
]}

Cui, Xiuyu ^{[1
,2
]}

Farber, S. Harrison ^{[1
,2
,7
]}

Woroniecka, Karolina ^{[1
,2
,3
]}

Elsamadicy, Aladine A. ^{[1
,2
]}

Dechant, Cosette A. ^{[1
,2
]}

Kemeny, Hanna R. ^{[1
,2
]}

Sanchez-Perez, Luis ^{[1
,2
]}

Cheema, Tooba A. ^{[8
]}

Souders, Nicholas C. ^{[9
]}

Herndon, James E. ^{[10
]}

Coumans, Jean-Valery ^{[11
,12
]}

Everitt, Jeffrey, I ^{[3
]}

Nahed, Brian, V ^{[11
,12
]}

Sampson, John H. ^{[1
,2
,3
,13
,14
]}

Gunn, Michael D. ^{[3
,14
,15
]}

Martuza, Robert L. ^{[11
,12
]}

Dranoff, Glenn ^{[16
]}

Curry, William T. ^{[11
,12
]}

Fecci, Peter E. ^{[1
,2
,3
]}

机构：

[1] Duke Univ, Med Ctr, Preston Robert Tisch Brain Tumor Ctr, Durham, NC 27708 USA

[2] Duke Univ, Med Ctr, Dept Neurosurg, Durham, NC 27708 USA

[3] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27708 USA

[4] Johns Hopkins Univ, Sch Med, Dept Neurosurg, Baltimore, MD 21205 USA

[5] Osaka Univ, Grad Sch Med, Dept Resp Med & Clin Immunol, Suita, Osaka, Japan

[6] Charite Med Univ, Dept Neurosurg, Berlin, Germany

[7] St Josephs Hosp, Barrow Neurol Inst, Dept Neurosurg, Phoenix, AZ USA

[8] Unum Therapeut, Cambridge, MA USA

[9] Dana Farber Canc Inst, Boston, MA 02115 USA

[10] Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC USA

[11] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA

[12] Harvard Med Sch, Boston, MA USA

[13] Duke Univ, Dept Radiat Oncol, Med Ctr, Durham, NC USA

[14] Duke Univ, Dept Immunol, Med Ctr, Durham, NC USA

[15] Duke Univ, Dept Med, Div Cardiol, Med Ctr, Durham, NC USA

[16] Novartis Inst Biomed Res, Cambridge, MA USA

来源：

NATURE MEDICINE | 2018年 / 24卷 / 09期

基金：

美国国家卫生研究院;

关键词：

PRIMARY BRAIN-TUMORS; S1P(1) RECEPTOR AGONIST; SPHINGOSINE; 1-PHOSPHATE; SPHINGOSINE-1-PHOSPHATE RECEPTOR-1; MALIGNANT GLIOMA; LYMPHOID ORGANS; IMMUNE DEFECTS; IMMUNOBIOLOGY; S1PR1; NEUROINFLAMMATION;

D O I：

10.1038/s41591-018-0135-2

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

T cell dysfunction contributes to tumor immune escape in patients with cancer and is particularly severe amidst glioblastoma (GBM). Among other defects, T cell lymphopenia is characteristic, yet often attributed to treatment. We reveal that even treatment-naive subjects and mice with GBM can harbor AIDS-level CD4 counts, as well as contracted, T cell-deficient lymphoid organs. Missing naive T cells are instead found sequestered in large numbers in the bone marrow. This phenomenon characterizes not only GBM but a variety of other cancers, although only when tumors are introduced into the intracranial compartment. T cell sequestration is accompanied by tumor-imposed loss of S1P1 from the T cell surface and is reversible upon precluding S1P1 internalization. In murine models of GBM, hindering S1P1 internalization and reversing sequestration licenses T cell-activating therapies that were previously ineffective. Sequestration of T cells in bone marrow is therefore a tumor-adaptive mode of T cell dysfunction, whose reversal may constitute a promising immunotherapeutic adjunct.

引用

页码：1459 / +

页数：12

共 45 条

[1]

A Metabolic Shift Favoring Sphingosine 1-Phosphate at the Expense of Ceramide Controls Glioblastoma Angiogenesis [J].