title: STAT3 inhibition for cancer therapy: Cell-autonomous effects only?
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.
authors.affiliation: Equipe 11 labellisée Ligue Nationale contre le Cancer, Center de Recherche des Cordeliers, Paris, France; INSERM, U1138, Paris, France; Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France; Université Pierre et Marie Curie/Paris VI, Paris, France; Metabolomics and Cell Biology Platforms, GustaveRoussy Comprehensive Cancer Center, Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.affiliation: Equipe 11 labellisée Ligue Nationale contre le Cancer, Center de Recherche des Cordeliers, Paris, France; INSERM, U1138, Paris, France; Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France; Université Pierre et Marie Curie/Paris VI, Paris, France; Gustave Roussy Comprehensive Cancer Center, Villejuif, France.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Galluzzi
authors.affiliation: Gustave Roussy Comprehensive Cancer Center, Villejuif, France; INSERM, U1015, Equipe labellisé e Ligue Nationale Contre le Cancer, Villejuif, France; University of Paris Sud/Paris XI, Le Kremlin-Bicêtre, France; Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507, Villejuif, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
keywords: AZD9150; IL-6; PD-1; checkpoint blockers; lymphoma; non-small cell lung carcinoma