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Sci Transl Med. 2019 Jul 17;11(501). pii: eaav7816. doi: 10.1126/scitranslmed.aav7816.

Sensitization to immune checkpoint blockade through activation of a STAT1/NK axis in the tumor microenvironment.

Author information

1
School of Biomedical Sciences, University of Western Australia, M503, Crawley, WA 6009, Australia.
2
National Centre for Asbestos Related Diseases, 5th Floor QQ Block, 6 Verdun Street, Nedlands, WA 6009, Australia.
3
Telethon Kids Institute, University of Western Australia, PO Box 855, West Perth, WA 6872, Australia.
4
Medical School, University of Western Australia, M503, Crawley, WA 6009, Australia.
5
Department of Medical Oncology, Sir Charles Gairdner Hospital, Hospital Ave, Nedlands, WA 6009, Australia.
6
Immunology and Virology Program, Centre for Ophthalmology and Visual Science, University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia.
7
Centre for Experimental Immunology, Lions Eye Institute, 2 Verdun Street, Nedlands, WA 6009, Australia.
8
Infection and Immunity Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, VIC 3800, Australia.
9
Department of Anatomical Pathology, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, WA 6009, Australia.
10
School of Mathematics and Statistics, University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia.
11
CSIRO, Mineral Resources, 26 Dick Perry Ave, Kensington, WA, 6152, Australia.
12
Bioceros, Yalelaan 46, Alexander Numan Building, 3584 CM Utrecht, Netherlands.
13
Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, University of Western Australia, 6 Verdun Street, Nedlands, WA 6009, Australia.
14
School of Biomedical Sciences, University of Western Australia, M503, Crawley, WA 6009, Australia. willem.lesterhuis@uwa.edu.au.

Abstract

Cancer immunotherapy using antibodies that target immune checkpoints has delivered outstanding results. However, responses only occur in a subset of patients, and it is not fully understood what biological processes determine an effective outcome. This lack of understanding hinders the development of rational combination treatments. We set out to define the pretreatment microenvironment associated with an effective outcome by using the fact that inbred mouse strains bearing monoclonal cancer cell line-derived tumors respond in a dichotomous manner to immune checkpoint blockade (ICB). We compared the cellular composition and gene expression profiles of responsive and nonresponsive tumors from mice before ICB and validated the findings in cohorts of patients with cancer treated with ICB antibodies. We found that responsive tumors were characterized by an inflammatory gene expression signature consistent with up-regulation of signal transducer and activator of transcription 1 (STAT1) and Toll-like receptor 3 (TLR3) signaling and down-regulation of interleukin-10 (IL-10) signaling. In addition, responsive tumors had more infiltrating-activated natural killer (NK) cells, which were necessary for response. Pretreatment of mice with large established tumors using the STAT1-activating cytokine interferon-γ (IFNγ), the TLR3 ligand poly(I:C), and an anti-IL-10 antibody sensitized tumors to ICB by attracting IFNγ-producing NK cells into the tumor, resulting in increased cure rates. Our results identify a pretreatment tumor microenvironment that predicts response to ICB, which can be therapeutically attained. These data suggest a biomarker-driven approach to patient management to establish whether a patient would benefit from treatment with sensitizing therapeutics before ICB.

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