authors contributed equally 2 One Sentence Summary: A STAT1-driven inflammatory phenotype associated with response to checkpoint blocking antibodies can be therapeutically attained and sensitizes cancers to immunotherapy. 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 utilizing 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 non-responsive tumors from mice before ICB, and validated the findings in cancer patient cohorts treated with antibodies targeting the PD-1/PD-L1 pathway. We found that responsive tumors were characterized by an inflammatory gene expression signature consistent with upregulation of STAT1 and TLR3 signaling, and down-regulation of IL-10 signaling. In addition, responsive tumors had more infiltrating activated natural killer (NK) cells, which were necessary for response. Pretreatment of different mouse strains with large established tumors, using a combination of the STAT1activating cytokine 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 cellular and molecular tumor microenvironment that predicts response to ICB, which can be therapeutically attained. This data anticipates a biomarker-driven approach to patient management to establish whether a patient would benefit from treatment with sensitizing therapeutics before ICB. Introduction:

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