STAT3 inhibition for cancer therapy: Cell-autonomous effects only?

Guido Kroemer, Lorenzo Galluzzi, Laurence Zitvogel

    Research output: Contribution to journalEditorial

    11 Citations (Scopus)

    Abstract

    A paper recently published in Science Translational Medicine describes a next-generation antisense oligonucleotide that specifically downregulates the expression of human signal transducer and activator of transcription 3 (STAT3). Such an oligonucleotide, AZD9150, exerts antineoplastic effects on a selected panel of STAT3-dependent human cancer cells growing in vitro and in vivo (as xenografts in immunodeficient mice). Moreover, preliminary data from a Phase I clinical trial indicate that AZD9150 may cause partial tumor regression in patients with chemorefractory lymphoma and non-small cell lung carcinoma. STAT3 not only participates in cell-autonomous processes that are required for the survival and growth of malignant cells, but also limits their ability to elicit anticancer immune responses. Moreover, STAT3 contribute to the establishment of an immunosuppressive tumor microenvironment. Thus, the inhibition of STAT3 may promote immunosurveillance by a dual mechanism: (1) it may increase the immunogenicity of cancer cells via cell-autonomous pathways; and (2) it may favor the reprogramming of the tumor microenvironment toward an immunostimulatory state. It will therefore be important to explore whether immunological biomarkers predict the efficacy of AZD9150 in the clinic. This may ameliorate patient stratification and it may pave the way for rational combination therapies involving classical chemotherapeutics with immunostimulatory effects, AZD9150 and immunotherapeutic agents such as checkpoint blockers.

    Original languageEnglish
    Article numbere1126063
    JournalOncoImmunology
    Volume5
    Issue number5
    DOIs
    Publication statusPublished - 3 May 2016

    Keywords

    • AZD9150
    • Checkpoint blockers
    • IL-6
    • Lymphoma
    • Non-small cell lung carcinoma
    • PD-1

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