title: STAT3 Establishes an Immunosuppressive Microenvironment during the Early Stages of Breast Carcinogenesis to Promote Tumor Growth and Metastasis.
abstract: Immunosurveillance constitutes the first step of cancer immunoediting in which developing malignant lesions are eliminated by antitumorigenic immune cells. However, the mechanisms by which neoplastic cells induce an immunosuppressive state to evade the immune response are still unclear. The transcription factor STAT3 has been implicated in breast carcinogenesis and tumor immunosuppression in advanced disease, but its involvement in early disease development has not been established. Here, we genetically ablated Stat3 in the tumor epithelia of the inducible PyVmT mammary tumor model and found that Stat3-deficient mice recapitulated the three phases of immunoediting: elimination, equilibrium, and escape. Pathologic analyses revealed that Stat3-deficient mice initially formed hyperplastic and early adenoma-like lesions that later completely regressed, thereby preventing the emergence of mammary tumors in the majority of animals. Furthermore, tumor regression was correlated with massive immune infiltration into the Stat3-deficient lesions, leading to their elimination. In a minority of animals, focal, nonmetastatic Stat3-deficient mammary tumors escaped immune surveillance after a long latency or equilibrium period. Taken together, our findings suggest that tumor epithelial expression of Stat3 plays a critical role in promoting an immunosuppressive tumor microenvironment during breast tumor initiation and progression, and prompt further investigation of Stat3-inhibitory strategies that may reactivate the immunosurveillance program.
authors.affiliation: Goodman Cancer Centre, McGill University, Montreal, Quebec, Canada. Departments of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Jones
authors.affiliation: Department of Pathology, University of California San Francisco, San Francisco, California.
authors.forename: Miranda L
authors.initials: ML
authors.lastname: Broz
authors.affiliation: Goodman Cancer Centre, McGill University, Montreal, Quebec, Canada. Departments of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: Jill J
authors.initials: JJ
authors.lastname: Ranger
authors.affiliation: Departments of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Ozcelik
authors.affiliation: Department of Oncology, McGill University, Montreal, Quebec, Canada. Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Ryuhjin
authors.initials: R
authors.lastname: Ahn
authors.affiliation: Goodman Cancer Centre, McGill University, Montreal, Quebec, Canada. Departments of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Zuo
authors.affiliation: Department of Oncology, McGill University, Montreal, Quebec, Canada. Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Josie
authors.initials: J
authors.lastname: Ursini-Siegel
authors.affiliation: Departments of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Hallett
authors.affiliation: Department of Pathology, University of California San Francisco, San Francisco, California.
authors.forename: Matthew
authors.initials: M
authors.lastname: Krummel
authors.affiliation: Goodman Cancer Centre, McGill University, Montreal, Quebec, Canada. Departments of Biochemistry, McGill University, Montreal, Quebec, Canada. William.muller@mcgill.ca.
authors.forename: William J
authors.initials: WJ
authors.lastname: Muller
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D005260:Female; D007108:Immune Tolerance / Q000502:physiology*; D007157:Immunologic Surveillance / Q000502:physiology*; D015674:Mammary Neoplasms, Animal / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis / Q000473:pathology*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000502:physiology*
chemical_list: D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse