Lin-CCR2+ hematopoietic stem and progenitor cells overcome resistance to PD-1 blockade

被引：35

作者：

Flores, Catherine T. ^{[1
]}

Wildes, Tyler J. ^{[1
]}

Drake, Jeffrey A. ^{[1
]}

Moore, Ginger L. ^{[1
]}

Dean, Bayli DiVita ^{[1
]}

Abraham, Rebecca S. ^{[1
]}

Mitchell, Duane A. ^{[1
]}

机构：

[1] Univ Florida, Brain Tumor Immunotherapy Program, Preston A Wells Jr Ctr Brain Tumor Therapy, Lillian S Wells Dept Neurosurg, 1149S Newell Dr,L2-100, Gainesville, FL 32611 USA

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

关键词：

CD8(+) T-CELLS; TUMOR MICROENVIRONMENT; CANCER-IMMUNOTHERAPY; DENDRITIC CELLS;

D O I：

10.1038/s41467-018-06182-5

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Immune checkpoint blockade using anti-PD-1 monoclonal antibodies has shown considerable promise in the treatment of solid tumors, but brain tumors remain notoriously refractory to treatment. In CNS malignancies that are completely resistant to PD-1 blockade, we found that bone marrow-derived, lineage-negative hematopoietic stem and progenitor cells (HSCs) that express C-C chemokine receptor type 2 (CCR2(+)) reverses treatment resistance and sensitizes mice to curative immunotherapy. HSC transfer with PD-1 blockade increases T-cell frequency and activation within tumors in preclinical models of glioblastoma and medulloblastoma. CCR2(+)HSCs preferentially migrate to intracranial brain tumors and differentiate into antigen-presenting cells within the tumor microenvironment and cross-present tumor-derived antigens to CD8(+) T cells. HSC transfer also rescues tumor resistance to adoptive cellular therapy in medulloblastoma and glioblastoma. Our studies demonstrate a novel role for CCR2(+)HSCs in overcoming brain tumor resistance to PD-1 checkpoint blockade and adoptive cellular therapy in multiple invasive brain tumor models.

引用

页数：14

共 17 条

[1] Dendritic cells pulsed with RNA are potent antigen-presenting cells in vitro and in vivo [J].