TY  - JOUR
AU  - Goswami, Sangeeta
AU  - Walle, Thomas
AU  - Cornish, Andrew E
AU  - Basu, Sreyashi
AU  - Anandhan, Swetha
AU  - Fernandez, Irina
AU  - Vence, Luis
AU  - Blando, Jorge
AU  - Zhao, Hao
AU  - Yadav, Shalini Singh
AU  - Ott, Martina
AU  - Kong, Ling Y
AU  - Heimberger, Amy B
AU  - de Groot, John
AU  - Sepesi, Boris
AU  - Overman, Michael
AU  - Kopetz, Scott
AU  - Allison, James P
AU  - Pe'er, Dana
AU  - Sharma, Padmanee
TI  - Immune profiling of human tumors identifies CD73 as a combinatorial target in glioblastoma.
JO  - Nature medicine
VL  - 26
IS  - 1
SN  - 1546-170X
CY  - New York, NY
PB  - Nature America Inc.
M1  - DKFZ-2020-00018
SP  - 39-46
PY  - 2020
N1  - 26 (1), 39-46Jan 2020 / #EA:E055#
AB  - 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 types1,2. 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 CD73hi 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:31873309
DO  - DOI:10.1038/s41591-019-0694-x
UR  - https://inrepo02.dkfz.de/record/148826
ER  -