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

Rachael Zemek, Emma de Jong, Melvin Chin, Iona Schuster, Vanessa Fear, Tom Casey, Catherine Forbes, Sarah Dart, Connull Leslie, Ayham Zaitouny, Michael Small, Louis Boon, Alistair R. R. Forrest, Daithi O Muiri, Mariapia Degli-Esposti, Michael Millward, Anna Nowak, Timo Lassmann, Anthony Bosco, Richard LakeWillem Lesterhuis

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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.
Original languageEnglish
Article numbereaav7816
Number of pages14
JournalScience Translational Medicine
Volume11
Issue number501
DOIs
Publication statusPublished - 17 Jul 2019

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