김대선 (University of Calgary, Alberta Children’s Hospital Research Institute, Arnie Charbonneau Cancer Institute) | 한빛사논문 > 한빛사

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조회569

University of Calgary, Alberta Children’s Hospital Research Institute, Arnie Charbonneau Cancer Institute

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Nat. Commun., Published: 24 August 2017, 8, Article number: 344 | DOI: 10.1038/s41467-017-00324-x Smac mimetics and oncolytic viruses synergize in driving anticancer T-cell responses through complementary mechanisms

Dae-Sun Kim^1,2,3, Himika Dastidar^1,2,3, Chunfen Zhang^1,2, Franz J. Zemp^1,2,3, Keith Lau^1,2,3,4, Matthias Ernst^1,2, Andrea Rakic^1,2,5, Saif Sikdar^1,2,3, Jahanara Rajwani^1,2, Victor Naumenko^1,2,3,4, Dale R. Balce6, Ben W. Ewanchuk⁷, Pankaj Tailor⁶, Robin M. Yates^6,7, Craig Jenne^3,4, Chris Gafuik^1,2,3 & Douglas J. Mahoney^1,2,3,7
¹Alberta Children’s Hospital Research Institute, Calgary, AB, Canada T2N 4N1. ² Arnie Charbonneau Cancer Institute, Calgary, AB, Canada T2N 4N1. ³ Department of Microbiology, Immunology and Infectious Disease, Faculty of Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1. ⁴ Snyder Institute for Chronic Disease, Calgary, AB, Canada T2N 4N1. ⁵ Department of Medical Sciences, Faculty of Medicine, University of Calgary, Calgary, AB,
Canada T2N 4N1. ⁶Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1. ⁷ Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1.

Correspondence and requests for materials should be addressed to D.J.M.

Abstract

Second mitochondrial activator of caspase (Smac)-mimetic compounds and oncolytic viruses were developed to kill cancer cells directly. However, Smac-mimetic compound and oncolytic virus therapies also modulate host immune responses in ways we hypothesized would complement one another in promoting anticancer T-cell immunity. We show that Smac-mimetic compound and oncolytic virus therapies synergize in driving CD8⁺ T-cell responses toward tumors through distinct activities. Smac-mimetic compound treatment with LCL161 reinvigorates exhausted CD8⁺ T cells within immunosuppressed tumors by targeting tumor-associated macrophages for M1-like polarization. Oncolytic virus treatment with vesicular stomatitis virus (VSV^ΔM51) promotes CD8⁺ T-cell accumulation within tumors and CD8⁺ T-cell activation within the tumor-draining lymph node. When combined, LCL161 and VSV^ΔM51 therapy engenders CD8⁺ T-cell-mediated tumor control in several aggressive mouse models of cancer. Smac-mimetic compound and oncolytic virus therapies are both in clinical development and their combination therapy represents a promising approach for promoting anticancer T-cell immunity.

논문정보

형식Research article
게재일2017년 08월 (BRIC 등록일 2018-08-08)
연구진국외 연구진
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