Immune profiling of human tumors identifies CD73 as a combinatorial target in glioblastoma

被引:289
作者
Goswami, Sangeeta [1 ]
Walle, Thomas [2 ,3 ]
Cornish, Andrew E. [4 ,5 ]
Basu, Sreyashi [6 ]
Anandhan, Swetha [1 ]
Fernandez, Irina [6 ]
Vence, Luis [6 ]
Blando, Jorge [6 ]
Zhao, Hao [6 ]
Yadav, Shalini Singh [6 ]
Ott, Martina [7 ]
Kong, Ling Y. [7 ]
Heimberger, Amy B. [7 ]
de Groot, John [8 ]
Sepesi, Boris [9 ]
Overman, Michael [10 ]
Kopetz, Scott [10 ]
Allison, James P. [6 ,11 ]
Pe'er, Dana [4 ]
Sharma, Padmanee [1 ,6 ,11 ]
机构
[1] Univ Texas MD Anderson Canc Ctr, Dept Genitourinary Med Oncol, Houston, TX 77030 USA
[2] Natl Ctr Tumor Dis, Dept Med Oncol, Heidelberg, Germany
[3] German Canc Res Ctr, Clin Cooperat Unit Mol Radiooncol, Heidelberg, Germany
[4] Sloan Kettering Inst, Computat & Syst Biol Program, New York, NY USA
[5] NYU, Sch Med, Dept Med, New York, NY USA
[6] Univ Texas MD Anderson Canc Ctr, Immunotherapy Platform, Houston, TX 77030 USA
[7] Univ Texas MD Anderson Canc Ctr, Dept Neurosurg, Houston, TX 77030 USA
[8] Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX 77030 USA
[9] Univ Texas MD Anderson Canc Ctr, Dept Thorac & Cardiovasc Surg, Houston, TX 77030 USA
[10] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA
[11] Univ Texas MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77030 USA
基金
美国国家卫生研究院;
关键词
NIVOLUMAB; CANCER; CELLS; VISUALIZATION; ANTI-CTLA-4; MULTICENTER; IPILIMUMAB; DOCETAXEL; CARCINOMA; THERAPY;
D O I
10.1038/s41591-019-0694-x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Immune checkpoint therapy with anti-CTLA-4 and anti-PD-1/PD-L1 has revolutionized the treatment of many solid tumors. However, the clinical efficacy of immune checkpoint therapy is limited to a subset of patients with specific tumor types(1,2). Multiple clinical trials with combinatorial immune checkpoint strategies are ongoing; however, the mechanistic rationale for tumor-specific targeting of immune checkpoints is elusive. To garner an insight into tumor-specific immunomodulatory targets, we analyzed 94 patients representing five different cancer types, including those that respond relatively well to immune checkpoint therapy and those that do not, such as glioblastoma multiforme, prostate cancer and colorectal cancer. Through mass cytometry and single-cell RNA sequencing, we identified a unique population of CD73(hi) macrophages in glioblastoma multiforme that persists after anti-PD-1 treatment. To test if targeting CD73 would be important for a successful combination strategy in glioblastoma multiforme, we performed reverse translational studies using CD73(-/-) mice. We found that the absence of CD73 improved survival in a murine model of glioblastoma multiforme treated with anti-CTLA-4 and anti-PD-1. Our data identified CD73 as a specific immunotherapeutic target to improve antitumor immune responses to immune checkpoint therapy in glioblastoma multiforme and demonstrate that comprehensive human and reverse translational studies can be used for rational design of combinatorial immune checkpoint strategies. Analysis of a mass cytometry dataset for different human solid tumors coupled with murine reverse translational experiments suggests that targeting CD73 could enhance the efficacy of checkpoint inhibitor therapy in glioblastoma.
引用
收藏
页码:39 / +
页数:22
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