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000148826 037__ $$aDKFZ-2020-00018
000148826 041__ $$aeng
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000148826 1001_ $$aGoswami, Sangeeta$$b0
000148826 245__ $$aImmune profiling of human tumors identifies CD73 as a combinatorial target in glioblastoma.
000148826 260__ $$aNew York, NY$$bNature America Inc.$$c2020
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000148826 500__ $$a26 (1), 39-46Jan 2020 / #EA:E055#
000148826 520__ $$aImmune 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.
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000148826 7001_ $$0P:(DE-He78)51635089578f68fc9efdb61e6a760b64$$aWalle, Thomas$$b1$$eFirst author
000148826 7001_ $$aCornish, Andrew E$$b2
000148826 7001_ $$aBasu, Sreyashi$$b3
000148826 7001_ $$aAnandhan, Swetha$$b4
000148826 7001_ $$aFernandez, Irina$$b5
000148826 7001_ $$aVence, Luis$$b6
000148826 7001_ $$aBlando, Jorge$$b7
000148826 7001_ $$aZhao, Hao$$b8
000148826 7001_ $$aYadav, Shalini Singh$$b9
000148826 7001_ $$aOtt, Martina$$b10
000148826 7001_ $$aKong, Ling Y$$b11
000148826 7001_ $$00000-0002-9970-8695$$aHeimberger, Amy B$$b12
000148826 7001_ $$ade Groot, John$$b13
000148826 7001_ $$aSepesi, Boris$$b14
000148826 7001_ $$aOverman, Michael$$b15
000148826 7001_ $$aKopetz, Scott$$b16
000148826 7001_ $$aAllison, James P$$b17
000148826 7001_ $$aPe'er, Dana$$b18
000148826 7001_ $$00000-0003-4658-055X$$aSharma, Padmanee$$b19
000148826 773__ $$0PERI:(DE-600)1484517-9$$a10.1038/s41591-019-0694-x$$n1$$p39-46$$tNature medicine$$v26$$x1546-170X$$y2020
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