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

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.

journal_name

Sci Transl Med

journal_title

Science translational medicine

authors

Zemek RM,De Jong E,Chin WL,Schuster IS,Fear VS,Casey TH,Forbes C,Dart SJ,Leslie C,Zaitouny A,Small M,Boon L,Forrest ARR,Muiri DO,Degli-Esposti MA,Millward MJ,Nowak AK,Lassmann T,Bosco A,Lake RA,Lesterhuis WJ

doi

10.1126/scitranslmed.aav7816

subject

Has Abstract

pub_date

2019-07-17 00:00:00

issue

501

eissn

1946-6234

issn

1946-6242

pii

11/501/eaav7816

journal_volume

11

pub_type

杂志文章

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